Advanced technologies and polymer materials for surgical sutures

Sterilization techniques used forsutures have also been discussed in this chapter.1.2 Polymers as suture materialsIn the past sutures made of natural materials like dried animal gut, ani

Advances in biopolymer based surgical sutures

Blessy Joseph1, Jemy James2, Nandakumar Kalarikkal3and

1

Business Innovation and Incubation (BIIC), Mahatma Gandhi University, Kottayam, Kerala, India;

2 University Bretagne Sud, Lorient, France; 3 International and Inter University Centre for Nanoscience and Nanotechnology, Mahatma Gandhi University, Kottayam, Kerala, India

1.1 Introduction

Over the years, there has been a dramatic growth of the wound closuremarket Traditionally materials like silk, cotton, horsehair, animal tendonsand intestines, and wire made of precious metals were in operative pro-cedures The limitations and risks associated with such wound closuredevices demanded the need for efficient and cost-effective techniques forwound healing Although there have been significant advances in tissueadhesives and other mechanical wound closure devices, sutures have beenthe preferred choice for surgeons Sutures can be defined as the materialsused to uphold tissues together normally after a trauma or surgery [1] Theycan be natural or synthetic materials that can provide adequate mechanicalstrength during tissue fixation The art of suturing can be found in theEgyptian mummified resins, in which they have used woolen threads, plantfibers, hair, and tendons Suturing techniques were documented in 500

Samhita [2].” Metal wires were first applied in the human body by Frenchphysicists Lapayode and Sicre in 1775 to set a broken humerus (upper armbone)[3]

A fundamental change was witnessed following Second World War,after which polymer sutures and stainless steel became superior The se-lection of suture material is dependent on the physical and biologicalcharacteristics of the suture as well as the type of tissue to be healed Suturesare made from synthetic or natural polymers Synthetic polymers are notreadily degradable They accumulate and can have a long-term detrimentaleffect on ecosystems The tunable physical characteristics of biopolymersmake them a reliable material for the fabrication of sutures Biopolymerscan be obtained from natural sources or synthesized chemically from

Advanced Technologies and Polymer Materials for Surgical Sutures

ISBN 978-0-12-819750-9 © 2023 Elsevier Ltd.

1

biological material or entirely biosynthesized by living organisms[4] Theyare easily biodegradable as they are obtained from renewable sources Theterm “biodegradation” generally refers to degradation by microorganisms.The polymer is broken down into carbon dioxide and water which formsfood for microorganisms[5] Biopolymers as surgical sutures have gainedconsiderable attention because of their unique properties like biocompat-ibility and biodegradability Biopolymers can adopt more precise and

defined 3D shapes and structures when compared to synthetic polymershaving more simple and random organization[6] This makes biopolymersattractive for in vivo applications They are generally classified into threecategories based on the nature of repeating units they are composed of(i) polysaccharides, often carbohydrate structures (cellulose, chitin, starch,alginate, etc.); (ii) polypeptides made of amino acids (collagen, actin), and(iii) polynucleotides deoxynucleic acid (DNA) and ribonucleic acid (RNA))(Fig 1.1) This chapter intends to provide an overview of the biopolymersused for suture fabrication, their physical and biological properties, and howthese properties facilitate wound repair Sterilization techniques used forsutures have also been discussed in this chapter

1.2 Polymers as suture materials

In the past sutures made of natural materials like dried animal gut, animalhair (e.g., horse hair), silk, tendons, and plant fibers (e.g., linen, cotton)were widely used [7,8] The technological advancements in polymer sci-ence paved way for the development of sutures with diverse materialshaving excellent mechanical and physical properties There has been alarge-scale expansion and evolution of the research and business in the area

of materials for biomedical applications Still, sutures and staples are themost used material in the biomedical industry Sutures are to be used in

Figure 1.1 Classi fication of biopolymers according to their structure.

reinforcement is highly essential Biopolymer based absorbable sutures aremuch preferred to nonabsorbable sutures Sutures are generally classified asabsorbable and nonabsorbable based on whether they degrade or not afterperforming the intended function Nonabsorbable sutures need to beremoved by doctors, hence causing additional discomfort to patients.Whereas absorbable sutures degrade within the body usually by hydrolysis

or with the aid of proteolytic enzymes[9]

1.3 Biopolymers

Environmental problems arise with the continued use of synthetic mers Intensive research has been carried out in this direction, possiblyreplacing synthetic polymers with natural ones As mentioned above,biopolymers are obtained from biological sources Hence, the use of bio-polymers offers an eco-friendly approach They are decomposed by mi-croorganisms or natural processes like availability of moisture, sunlight, etc.which is environmentally friendly when compared to petroleum basedsynthetic polymers releasing toxic byproducts into the surroundings Bio-polymers are employed in diversified fields such as food packaging, drugdelivery, tissue engineering, etc Although they are biocompatible, many ofthem lack sufficient mechanical properties desired for medical applications.Most often they are crosslinked or modified with materials like glutaral-dehyde, citric acid, poly (carboxylic acids), and so forth[10] Crosslinkerslike glutaraldehyde can be cytotoxic hence greener approaches are alsobeing explored Nanoparticles are also used to enhance the properties ofbiopolymers The interaction between biopolymers and nanoparticles re-sults in nanocomposites with improved functionalities like antimicrobialproperty, tensile strength, thermal stability, or water resistance Many re-searchers have investigated the ability of silver nanoparticles (AgNPs ) toimprove the antimicrobial properties of biopolymers, wherein cost-effectivemethodologies could be formulated for developing wound dressings orfood packagingfilms Cellulose paper coated with silver-gold nanoparticlesdisplayed improved antibacterial activity against E.coli [11] Another workreported the synthesis of silver-cellulose hybrids which showed excellentantibacterial activity against E.coli and S.aureus whereas pure cellulose(Microcrystalline cellulose) didn’t exhibit any activity against the respectivemicrobial strains[12] Although several biopolymers find promising appli-cations in the biomedical sector, we will be concentrating on polymers likecellulose, collagen, silk, chitosan, chitin, polyhydroxyalkanoates (PHA), andPLA which particularlyfit well for the suture industry

poly-Cellulose is the naturally occurring homopolymer consisting ofb-1, 4linked glucan chains Being inherently biodegradable and low-cost material,cellulosefinds immense application in healthcare [13] Cellulose materialstry to self-assemble and form an extended network by both intramolecularand intermolecular hydrogen bonds, which makes them relatively stable.Chitin is a sustainable biopolymer due to its abundance Structurally,chitin is N-acetyl glucosamine and the main source are crustaceans likecrabs, shellfish, etc The deacylated form of chitin known as chitosanconsists of N-acetyl glucosamine and glucosamine moieties Both chitin andchitosan are versatile enough to be processed to any form like sponges, gels,

or scaffolds, thereby finding many applications in tissue engineering anddrug delivery[14] Natural silk fibers are produced by arthropods likesilkworms or spider Mulberry silkworms (Bombyx mori) are mostcommonly reared to produce silk They have a core-shell structure con-sisting of 3 components, a heavy chainfibroin, a light chain fibroin, and athird small glycoprotein, known as the P25 protein These proteins arecoated with hydrophilic sericins Silk materials are used as sponges,films, orsutures for applications like ligament tissue engineering, hepatic tissue en-gineering, cartilage tissue engineering, and so on [15e17] Poly(lactic acid)(PLA) is a biodegradable polyester produced from the monomer, lactic acid(LA) by mechanisms like direct polycondensation (DP) and ring-openingpolymerization (ROP) The tunable physicochemical properties andbiocompatibility of PLA make it suitable for biomedical applications.Collagen is a major structural protein in animals and forms a vital part of theextracellular matrix It provides tensile strength to tendons and ligamentsand also elasticity to the skin It has a 3D architecture comprising of a right-handed bundle of three parallel, left-handed poly proline II-type helices[18] Source of collagen includes bovine skin and tendons, porcine skin,marine organisms like sponges,fish, and jelly fish It is used for soft tissuerepair, dental applications, and as scaffolds for tissue engineering [19,20].Polyhydroxyalkanoates (PHA) are naturally synthesized polyesters accu-mulated as energy storage material inside the cellular structure of variousmicroorganisms

1.4 Biopolymers for sutures

1.4.1 Collagen

Collagen nanofibrils (CoNF) have a great potential for being mechanicallystrong but biodegradable sutures They play a major role in tissue

engineering as being the key component of the extracellular matrix It is themost abundant protein in the human body and imparts structural integrityand strength to the tissues[21] The use of collagen as a modern biomaterialbegan in 1881 Joseph Lister and William Macewen (Fig 1.2) reported theadvantages of catgut, a collagen-rich biomaterial prepared from the smallintestine of sheep[23] Untreated catgut sutures are often processed fromdead animal tissue, hence causing infections[24] They are often used in thecase of subcutaneous or fatty tissue[25] Collagen sutures were modifiedwith heparin for sustained release of platelet-derived growth factor-BB(PDGF-BB) Tendon-derived cells seeded on PDGF-BB incorporatedcollagen sutures showed 50% greater proliferation than untreated collagensutures[26] This could be because collagen provides active chemical sitesfor conjugating growth factors Collagen has also been used to coat surgicalsutures to improve their functionalities Polyester/polyethylene suturescoated with collagen were evaluated for their response to bone and tendoncells[27] Collagen coating was found to stimulate proliferation and adhe-sion of cells in collagen coated sutures when compared to uncoated one.

1.4.2 Polylactic acid (PLA)

PLA is one of the most popular biodegradable and bio-based polymers.PLA is used to prepare biodegradable polymer sutures [28] The biocom-patibility of the polymers has been extensively studied, and it has beenproven to be one of the best biopolymers for biomedical applications likesutures etc [29] PLA is a polymer derived from LA and its structure makes

it easily breakable during metabolism and thereby making it easier to beexcreted from the body [30] Degradation occurs through enzymatic orhydrolytic scission of ester bonds The degradation of PLA depends on its

Figure 1.2 SEM images of PLA suture loaded with PM-Ds: (A) 100
times, (B) 1000
times (Reproduced with permission from Ref [ 22 ].)

molecular weight, crystallinity, presence offillers, etc Recently, Liu et al.reported the fabrication of PLA sutures loaded with PLA microspherescontaining drug[22] Initially PLA microspheres containing drug genta-micin sulfate was prepared (PM-Ds) Further, this drug loaded microsphereswere loaded onto the PLA sutures (PM-Ds/PLA) The mechanical prop-erties were analyzed which showed an increase in the properties of the drugloaded suture when compared to the neat suture A sustained release of thedrug up to 8 days could be achieved As evident from the scanning electronmicroscopy images, the microspheres entered the gaps of the suturefibers,and stuck to them firmly which could have resulted in the prolongedrelease of the drug (Fig 1.2).

In another study, biopolymers like chitosan, alginate, and the blends ofthese polymers were coated on the surface of PLA sutures The mechanicalstudies were carried out Some of the drugs based on antibiotic sensitivitywas chosen and was introduced into the sutures using surface treatmentmethod like dip coating The drug release studies and antimicrobial activityproved that the drug-coated bio polymeric sutures were effective in woundclosing and wound healing [31] Poor biocompatibility and cellular affinityare major problem encountered with PLA sutures To improve the surfacehydrophilicity, PLA sutures were initially treated with lipase followed bygrafting with chitosan [32] It’s evident from the SEM images that initiallythe untreated sutures had a smooth surface Once grafted with chitosan, insome places chitosan united and led to a rougher surface and large frictioncoefficient However, hydrophilicity was greatly improved

Blends of PLA and polycaprolactone compatibilized with Ethyl EsterLLysine Triisocyanate (LTI) were melt-spun to produce suture threads ofdiameter 0.3 mm 1.0 phr of LTI was found to be the most suitablecomposition for producing sutures, at higher loadings the sutures were toorigid The suture threads didn’t induce any bacterial growth [33]

-1.4.3 Silk

Silk is a protein polymer whose characteristics are slow degradation andgood mechanical strength Silk is preferred for cardiovascular, neurological,and ophthalmic procedures [34] The ease of handling and improved knotsecurity properties makes silk superior among other sutures But their use ishindered due to the high inflammatory reactions posed by them [35,36].Bacterial attachment to silk sutures was compared to commercially availableMonocryl Plus suture [37] From Fig 1.3 it is evident that the

microorganisms were highly colonized around the suture knot of silk suturewhen compared to that of Monocryl Plus suture.

Maintaining sterile conditions in the wound has always been a hurdleafter suturing Medical devices and sutures contribute about 45% ofnosocomial infections or hospital-acquired infections [38] Antibacterialsutures play a pivotal role in combating surgical site infections[39] Once abiofilm is formed on the surface of a suture, it becomes resistant to tradi-tional antimicrobials

Once bacteria colonize a suture, local methods to treat bacterial fections become inadequate Hence, several strategies to prevent bacterialadherence have been proposed by researchers including the addition ofantibiotics, nanoparticles, biomaterials, etc Sutures impregnated with an-tibiotics have been found to prevent the adherence of bacteria and biofilmformation [40]

in-Tetracycline hydrochloride (TCH), a bacteriostatic drug is found toexhibit activity against a wide range of gram-positive and gram-negativemicroorganisms[41] The efficacy of TCH-treated sutures was studied byViju and Thilagavathi [42] As was expected, untreated silk sutures promotethe growth of E.coli and S.aureus

Synergistic chitosan and TCH drug was exploited to develop crobial silk sutures for preventing microbial infections [43] Such combi-nations can provide a prolonged antibacterial effect AgNPs have beenwidely used as an antibacterial agent[44,45] AgNPs exhibits their antimi-crobial potential through various mechanisms The anchoring of AgNPs to

antimi-Figure 1.3 Scanning electron microscope images of (A) silk suture knot material and (B) Monocryl Plus suture knot material Microorganisms and cellular detritus are highly visible in silk sutures (Reproduced with permission from Ref [ 37 ].)

microbial cells, followed by penetration into the cells, reactive oxygenspecies and free radical generation, and modulation of microbial signaltransduction pathways have been recognized as the most prominent ways ofantimicrobial action [46] AgNPs were coated on silk sutures to impartantibacterial properties [47] Mechanical strength was retained after theaddition of AgNPs; however, a significant reduction in bacterial growthwas achieved Cytotoxicity studies using 3T3 mouse embryonic fibroblastcells showed 82% cell viability for silver treated samples This showed thatthe silver treatment did not affect their proliferative capacity.

Surface modification of silk fibroin suture, AASF (antheraea assama,popularly known as golden silk; found only in certain parts of Assam) wasachieved by grafting polypropylene (PP) onto silkfibroin sutures[48] Herethe sutures were first sterilized using argon and then low-temperatureplasma grafting of PP onto sterilized sutures was done to achieve thedesired biofunctionalities Here the modified suture showed morebiocompatibility and improved wound healing when compared to theuntreated ones In vivo studies were conducted in three groups The firstgroup was sutured with AASF, the second with argon plasma-treated AASF(AASFAr) and the third group with PP grafted AASF sutures (PP-AASF).The histopathology studies on the 14th postoperative day show the pres-ence of inflammatory cells in group A characterized by lesser collagenformation (Fig 1.4) Group B shows a considerably fair amount of collagenformation with slight infiltration in and around hair follicles Whereas PP-AASF sutured group (Group C) shows highly accelerated wound healingactivity Moreover, a greater amount of hair follicles was also present whencompared to the other groups

Figure 1.4 Histologic evaluation of wound healing on 14th postoperative day topathological section of the sample collected from the incised wound of (A) group A, (B) group B, and (C) group C animals shows inflammatory cell inflammation (IN) in and around the hair follicle (HF) as well as subepidermal tissue Proliferation of fibrous connective tissue (CT) indicates faster healing of group B and group C as compared to group A animals (Reproduced with permission from Ref [ 48 ].)

His-1.4.4 Chitin & chitosan

Chitin and chitosan are polymers derived from marine animals and is some

of the most available biopolymers other than cellulose However, some ofthe challenges make its usage cumbersome [49] Though chitin is highlybiocompatible, nontoxic, and biodegradable, along with its antimicrobialeffect, there are still more challenges to overcome to exploit its huge po-tential for prospective applications [50] Chitosan is a potent antimicrobialagent and its antimicrobial activity can be attributed to its cationic nature[51] The positively charged chitosan molecules interact with negativelycharged microbial cell membranes leading to the disruption of the microbialmembrane [52] Sutures were fabricated from chitin having good me-chanical strength [53] No allergic reactions or inflammation was seen Thechitin suture was absorbed in about 4 months in rat muscles The accel-erated degradation can be mainly due to the action of lysozyme Chitinnanofibrils are used as nanofillers for reinforcing polymers to obtainnanocomposites with enhanced stability, especially in the case of bio-resorbable sutures [54] Chitosan stimulates tissue regeneration and preventsscar formation The mechanical strength of chitosan is very low; hence, it ismainly exploited as suture coatings Chitosan has been used for coating silksutures [55] Silk sutures coated with chitosan also showed excellent anti-bacterial efficacy [56] A modified derivative of chitosan known as hydroxylpropyl trimethyl ammonium chloride (HACC) chitosan coated on Vicrylsuture showed excellent antibacterial activity and also displayed goodbiocompatibility [57] HACC is a water-soluble modified derivative ofchitosan that exhibits good antibacterial activity [58,59] HACC coatedsutures effectively prevented biofilm formation when compared totriclosan-coated sutures Prabha et al showed that extracted chitosan (EC)from crab shells showed higher inhibition of biofilm formed by mixedspecies[60] The antibacterial and antifungal effects of Vicryl absorbablesutures coated with chitosan, uncoated sutures, and commercially availabletriclosan-coated sutures were studied against S epidermidis and C albicans(Fig 1.5) The uncoated suture (control) and sutures soaked with acetic acid(Vehicle control) did not show any antibacterial or anticandidal activity.The commercial triclosan-coated sutures exhibited only antibacterial ac-tivity and did not show any anticandidal activity EC immobilized suturesexhibited good antimicrobial activity against both strains compared tocommercially available chitosan (CC)

1.4.5 Polyhydroxyalkanoate (PHA)

PHA is a microbial polyester having excellent biocompatibility andbiodegradability Poly(3-hydroxybutyrate) (PHB) is the most widespreadmember of the polyhydroxyalkanoate family and is produced under un-balanced growth conditions like depletion of essential nutrients such asnitrogen, phosphorus, or magnesium [61] Poly (4-hydroxybutyrate)(P4HB) is a typical PHA type used for the fabrication of surgical materials.The most well-known product, and thefirst approved by the US Food andDrug Administration, is the TephaFLEX suture fabricated from P4HB [62]

In vivo studies of PHA sutures implanted intramuscularly over 1 yearshowed that animals that received the sutures were in good health condi-tion during the period of study No adverse reactions were observed, andfunctional characteristics of the animals were also not affected [63] Poly-hydroxyalkanoate sutures decreased tendency to curl were fabricated byextrusion and orientation of the fibers [64] The resulting fibers had anelongation to break from about 17% to about 85% and Young’s modulus ofless than 350,000 psi He et al evaluated the biocompatibility of mono-filament made from poly (3-hydroxybutyrate-co-3-hydroxyhexanoate)(PHBHHx) and a multifilament made from poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and PLA blend [65] The PHBHHxfiber and thePHBV/PLA fiber showed remarkable biocompatibility to be used as sur-gical sutures

Figure 1.5 Antimicrobial activities of the impregnated suture against S epidermidis and C albicans: (A) Control; (B) VC; (C) EC (400 mg/mL); (D) CC (400 & 450 mg/mL); (E) Triclosan coated Reproduced with permission from Ref [ 60 ].

1.4.6 Cellulose

Plants are the major source of cellulose, the most abundant and easilyavailable carbohydrate polymer on earth Bacterial cellulose, an alternateand highly purified form of cellulose is produced by aerobic bacteria,mainly of the genus Acetobacter [66] Their unique nanostructure, excel-lent water retaining capacity, good mechanical strength, and high crystal-linity makes them preferred choice in biomedical applications [67].Bacterial cellulose nanocrystals (BCNC) were used to reinforce chitin (RC)fibers to form BCNC/RC yarns[68] The fibers were produced by wetspinning technology for application as surgical sutures In vitro studiesshowed good biocompatibility and in vivo studies revealed good woundhealing with BC coated yarns However, the knot pull tensile strength of allcoated yarns was lower than uncoated ones

Oxidized cellulose is highly biocompatible and has great antibacterialproperties against a variety of pathogens The ability of oxidized cellulose assuture material was studied by Li et al who explored the effect of tempooxidation treatment on the physical and mechanical properties of TORC(TEMPO-mediated oxidation of regenerated cellulose) sutures [69] Thecarboxyl content in the suture materials was controlled by varied oxidationtimes It could be seen that TEMPO oxidation significantly influenced thedegradation of sutures as evaluated from the hydrolysis test performed byimmersing the sutures in physiological saline for 7, 14, 21, and 28 days(Fig 1.6) The carboxyl groups introduced in the sutures due to TEMPO

Figure 1.6 The in the vitro degradation rate of TORC and different TORC at different oxidation times (15, 30, 45, 60, and 90 min after PBS impregnation (mean  S.D.,

n ¼ 10)) (Reproduced with permission from [ 69 ].)

oxidation leads to increased molecular chain spacing and reduction inmolecular interatomic force whereby water easily penetrates the fiberresulting in breakage.

1.5 Sterilization of sutures

Sterilization technology plays a prominent role in the biomedical fieldbecause bacterial colonization remains a big problem with medical implants ordevices Every surgical procedure is associated with a certain risk ofcontamination and hence the sutures must be well sterilized to preventbacterial adherence Despite the widespread use of sutures in the 19th century,suture associated infections were a major concern Lord Joseph Lister maderemarkable contributions to the history of sterilization [2] He pointed outthat whatever be the cause of wound infection, carbolic acid could prevent orhalt its further progress [70].In 1869, he developed aseptic silk sutures treatedwith carbolic acid followed by sutures from sheep intestine known as catgutsutures(catgut sutures treated with 5% chromic acid)

Claudius introduced the concept of using potassium iodide for suturesterilization in 1902, and the infection rate was further reduced [71] A processfor sterilizing catgut sutures and ligatures using heat was invented in 1958 [72].Here catgut sutures and ligatures sealed in a container in the presence ofaqueous isopropanol solution were sterilized by heat Ethicon Inc startedusing electron beam accelerators for suture sterilization in 1957 [73].According to the European Norm 556 sterility is defined as the state ofbeing free from viable microorganisms (1
10e6)[74] Generally, sterili-zation techniques can be classified as physical and chemical Physical steriliza-tion involves sterilization using heat and radiations whereas chemicalsterilization involves the use of chemicals like ethylene oxide, hydrogenperoxide, formaldehyde,b-propiolactone, etc Certain sterilization proceduresresult in stiffening of sutures and hence the selection of appropriate sterilizationtechniques is critical The tensile strength of Virgin silk suture treated bythermal methods of sterilization was found to decrease [75] Sterilization ofcollagen sutures withb-propiolactone showed no significant loss of strength ofthefinished sutures, hence can be used as an alternative to heat sterilization[76]

1.6 Conclusion and future perspectives

The growing environmental concerns have led to increased research in thefield of biopolymers Natural polymers or biopolymers are derived from

living organisms These have the added advantage of being biodegradable,biocompatible, renewable, and reduced antigenicity Sutures are materials

handling and biocompatibility, the mechanical properties of suture materialsare a major factor that affects the overall suture quality

Despite the modern technological advancements in the materials in themethodology perspectives, biopolymeric sutures have an important role inwound healing The progressive techniques like onsite evaluation of thewound healing, easy to use sutures or wound closure methods, smart sutures,and other wound closure devices and products are to be looked up in thefuture No sutures can be called ideal as such The vital concern is surgical siteinfection after surgery Although antibacterial sutures delivering antibioticshave been developed, maintaining all desirable biological and morphologicalfeatures in a single suture is still a matter of research The growing misuse ofantibiotics requires more alternatives to combat surgical site infections.The merging of the biopolymeric sutures and nanotechnology will give

a boost to the surgical industry where properties like better antimicrobialactivity, faster wound healing, etc could be achieved The inventions andinnovations in suture fabrication have a huge potential to be applied for thebetterment of the patients and making their lives better

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Functionalization of sutures

Felipe López-Saucedo1, Alejandro Ramos-Ballesteros2and

Emilio Bucio1

1

Departamento de Química de Radiaciones y Radioquímica, Instituto de Ciencias Nucleares,

Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, CDMX, Mexico;

2 Notre Dame Radiation Laboratory, University of Notre Dame, Indiana, United States

2.1 Introduction

It is well known that postoperative infections, and complications derivedfrom them, are among the main causes that delay and lengthen the healingprocess Postoperative infections are recurrent and responsible for a pro-longed hospital stay, extra intake of antibiotics, and, if the infectionprogress, additional surgeries and treatments that may cause death Thisissue is a worldwide concern to solve, and several efforts have been made tooptimize the postoperative phase since it is as important as the surgery itself.Although it is known that the causes of infection are diverse, suturing isparticularly relevant because the zone exposed to the intervention is sus-ceptible to pathogenic attacks hosted on the suture surface [1] Biohazardusually occurs at the time of insertion by contact with opportunistic skinmicroorganisms, but also for the migration of microorganisms from pre-existing foci of infection in the patient

A suture thread is a biomedical device (natural or synthetic) allocated toconnect blood vessels or to approximate tissues to accelerate healing Su-tures are widely used in surgery above other methods such as staples, tapes,

or laser cautery [2] due to easy sterilization, multipurpose, flexibility,handling, strong knotting, strain at rupture, elastic modulus, hypoallergenic,and ability to avoid the formation of biofilms around suture [3]

In previous sections were also summarized the desirable characteristicsthat materials for suture threads should comply like:

❖ High biocompatibility and nontoxicity

❖ Easy manipulation for the surgeon (folding, knotting, etc.)

❖ Easy sterilization without compromising material integrity

❖ Hypoallergenic

❖ Absorbable upon completion of its function (preferably)

❖ Inhibit bacterial growth

Advanced Technologies and Polymer Materials for Surgical Sutures

ISBN 978-0-12-819750-9 © 2023 Elsevier Ltd.

19

It is precisely the latter feature (antibacterial activity), where a highvolume of research has been focused lately on some researches where it isachieved.

One of the possible solutions to decrease bacterial growth (and thereforeinfections) is using suture threads with an agent to inhibit bacterial growth

in a localized and long-lasting manner [4,5] The inclusion of superficialagents adds new properties to the existing ones, enhancing efficiency andsafety, and fortunately, the functionalization achieves excellent resultswithout compromising the integrity of the polymeric suture threads.Currently, there is no ideal material able to cover all the required properties,therefore, the surgeon must choose among the assortment of suture ma-terials according to the type of wound, length, organ, exposition, andpatient condition [6] In addition to this, surgical interventions expose theskin tissue to damage, and, consequently, marks and/or scars can be per-manent, so the aesthetic variable must also be considered

The objectives of suture modification are based on finding and dardizing experimental methodologies, as well as comparing characteristicssuch as biocompatibility, susceptibility to biofilm proliferation and toxicity

stan-of materials before and after their processing [7] Suture functionalizationincludes various strategies going from impregnation and coatings to thosemethods where the surface is modified using high-energy radiation, such asplasma treatment or gamma radiation

2.2 Suture materials: from hairs to antibacterial

biopolymers

Since ancient times, humanity has used cotton ties, hair, and other naturalfibers to approximate tissues Egyptian civilization at the dawn of 3000B.C., employed different types of cords for mummification, but it is notdiscarded the use of threads for medical purposes [8] In Arabia, around 900B.C., surgical procedures were perfectioned and animal-origin absorbablesutures equivalent to modern catgut were used Meanwhile in India,around 600 and 500 B.C., the Sushruta Samhita (Sanskrit text on medicineand surgery) already recommended the use of different suture materialsincluding cotton, leather, and even horsehair; as well as other suturetechniques that were compiled and described in one of thefirst medicinemanuscripts ever [9] In Europe, Galen of Pergamum (129e201 A.D.),who lived in the region of present-day Turkey, wrote several books on theuse of sutures in surgical procedures, which turned into the annals of the

occidental medicine in the Classical Age By the Middle Age, silk suturesbegan to be used, this is a naturalfiber formed by a nonabsorbable polymer.Already in contemporary times, in the early 20th century, Dr WilliamHalstead (1852e1922), who was a pioneer of modern surgery in theUnited States, recommended the use of silk sutures and even tested withsilver sutures threads in hernia surgeries [10].

Starting the first half of the 20th century, during “the boom” of theexploration and exploitation of oil derivatives, many polymer materialsbegan to be developed and were proved in a variety of products, includingthe first synthetic sutures At this time in history, it was forward in thedesign of thefirst synthetic suture polymers; for example, the first methodsfor obtaining polyamides and polyesters were established, moreover,increasing demand for materials such as polypropylene (PP) allowed theproduction of strong suture monofilaments [11]

Undoubtedly, necessity is the mother of invention, and with humanity’sprogress, the optimization of sutures has become evident There is still along way to go, but thanks to the new techniques of surface modification, itseems that the path is traced With functionalization, not only the inherentproperties of the original material are preserved, like hardness, flexibility,thermal and chemical resistance, but also new features are added includinghydrophilicity, charge, surface area, and antimicrobial properties

2.3 Suture types

Surface modification and specific functionalization of sutures depend oncomposition and application If the suture is natural or synthetic, thefunctional groups at the surface will be susceptible to different reactions;therefore, different methods are required Suture threads are classified ac-cording to several criteria, but the most common are biodegradability,origin, and macroscopic structure (Table 2.1)

Table 2.1 Suture classi fication.

Suture thread

Degradability Absorbable Nonabsorbable

Origin Natural Synthetic

Metallic No metallic (organics) Structure Monofilament Multifilament

The monofilament sutures, as their name suggests, consist of a uniquefiber This configuration is adequate to prevent biofilm’s growth since it has

a uniform surface; while the multifilament suture is made up of severaltwisted or intertwined filaments, making them prone to lodge microor-ganisms in the larger superficial area However, monofilaments have lessresistance to suturing compared to multifilaments that have a higher frictioncoefficient Although in favor of multifilament sutures, they display greatertensile strength, firmer knot tying, and easier handling Also, themultifilament-type suture generally has better flexibility and is easier to tiecompared to the monofilament suture [2,9] For pragmatic purposes of thisdocument, the functionalization of absorbable and nonabsorbable sutures isdiscussed in detail in the next sections

2.4 Biocompatibility studies for functionalized

sutures

In vitro studies for functionalized sutures are necessary to assess toxicity andpossible adverse reactions Therefore, the progression for new materialdevelopment after synthesis and characterization implies cytotoxicity studies

to verify if these materials are compatible with humans [12] These tests, inconjunction with complementary (physical-chemical-mechanical proper-ties), help to discern viability for specific functionalization In the case ofsuture thread modifications also is monitored the possible changes thatoccurred compared with the pristine suture threads Tests to determine thebiocompatibility of materials are usually carried out in human andmammalian cell lines; for example, one of the most used is the embryonictissue cell line from mousefibroblasts (Mus musculus) BALB 3T3 This cellline is widely used as primary control because of its extreme sensitivity, andinherent capacity to be easily inhibited by contact with surrounding toxicsubstances [13] There are pre-established qualitative and quantitative kitsthat help to identify toxic or biocompatible materials or drugs One of thesekits to determine cell proliferation is the WST-1 assay This is a colorimetrictest that spectrophotometrically quantifies tetrazolium salts that aredegraded to formazan by the biological functions of the cell The chemical

4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolium]-1,3-benzene disulfonate, a molecule that degrades through acomplex mitochondrial succinate-tetrazolium-reductase system, which isonly active in living cell mitochondria [14]

Another staining-based indicator used for cell viability bioassays is thereagent resazurin, traded under the name Alamar Blue from ThermoFicherUSA, which is blue in color and is irreversibly reduced to the resofurincompound, which is red This reagent has been tried in a range of biologicalsystems and different cell types such as bacteria, fungi, protozoa, andcultured mammalian cells [15] Although quantification of cytotoxicity may

be calculated by measuring the “maximum noncytotoxic concentration”(limit at which there is not an alteration in the cell morphology andmetabolism), the parameter known as 50% cytotoxic inhibitory concen-tration (CI50%) is the most used CI50% is defined as the concentration oflethality for half of the cells, compared with controls and a blank [16].Regarding suture materials grafted with vinyl monomers such as

N-isopropylacrylamide (NIPAAm) [17], glycidyl methacrylate (GMA), oracrylic acid (AAc) [18], it has been verified with cytocompatibility studiesthat functionalization does not promote the formation and proliferation ofbiofilms (i.e., bacteria colonies) For this reason and biocompatibilityproperties, derived hydrophilic polymers are used in the manufacture ofseveral biomedical devices [19]

2.5 Functionalization

The functionalization of surface in suture threads is generally performedthrough two approaches: coating and graft functionalization Each withspecial characteristics according to the intended use of the final product,besides, some matrices are not prone to be functionalized (or coated) due tothe charge, polarity, hydrophilicity, or chemical resistance of thecomponents

2.5.1 Coating in fibers

The definition of coating is the covering of any surface It is characterizedbecause there are no significant changes in the inner composition of themodified material, and the coating usually does not cause a drastic change inthe mechanical properties, being the main objective of coatings only toachieve a difference in the reactivity of the surface and protection (toprevent corrosion) In other words, a coating is conducted for a pragmaticimprovement in the surface reactivity without compromising other parts ofthe material [20]

Concerning fiber-structured materials, the techniques have beenadapted to the development of tailored sutures Coatings in suture threadsare directed to increase the lifetime, minimize the tissue damage, andstimulate the cell recovery, but mainly to provide antibacterial features indrug-delivery systems The different techniques used for the coating offibers allow acquiring specific features, some alternatives of dip-coating andelectrodeposition are mentioned below It is important to mention thateven though coatings increase resistance and add new features to the ma-terial, does not present synergy or mutually enhanced properties that comefrom the chemical combination that functionalization provides.

2.5.1.1 Dip-coating

Dip-coating applied in suture threads is like dip processes infilms or pellets.This is the simplest fundament to achieve a uniform coating containing abioactive molecule The procedure consists of preparing a dissolution withthe bioactive principle in an adequate liquid medium, and subsequently,carried to dryness or it is submitted to curing It is expected that thecompound of interest remained attached to the surface of the materialwithout decomposing [21] In other words, the molecule of interest isdissolved, and then a third component is added, which plays a double role

of adhesive agent (to the surface of the material) and agglutinant (with thebioactive molecule) The reaction conditions such as pH or ionic strengthmay be easily controlled to increase the electrostatic interactions of thecoating with the surface of the material and promote layer growth Be-tween the layers, at the interface, there are partial positive and negativecharges whose interactions are responsible to keep the suture in one pieceduring and after the surgical procedure, but at the same time, keepingenough reactivity for a successful controlled release Examples of dip-coating in absorbable sutures illustrate better this principle (Fig 2.1)

In the first example, vicryl suture threads were coated with a blend ofcollagen and gentamicin; the protein and the antibiotic were dissolved inacetic acid The system works as follows: the gentamicin is embedded in thecollagen coating, while the collagen is well adhered to the surface of thesuture, leading this way to an antibacterial absorbable suture [22] Inanother example, the coating of a suture was performed using a bio-macromolecule, the messenger RNA, which was loaded directly ontopoly(lactide-co-glycolic acid), (PLGA) threads The mRNA is loaded tostimulate the regeneration of epidermal tissue; the composite mRNA-PLGA activates the expression of growth factors in the human

keratinocyte cell line (HaCat) This coating was carried out by dissolvingthe mRNA in a stock solution of PLGA/ethyl acetate Afterwards, themRNA was properly treated dropwise with the plasmid transfection agentsViromer RED or Lipofectamine 2000 The whole procedure is achieved atroom temperature [23].

2.5.1.2 Electrodeposition

It is an electrochemical method employed to produce metallic coatings

in situ In this process, colloids or nanoparticles are formed in solution andattached to the fiber, shaping a layer This method is perfect for themodification of metal threads Recently a copper wire was coated with Niusing electrodeposition, the Ni layer allowed the loading of TiO2 nano-particles in a homogeneous distribution along the wire surface; this coatingwould be useful for antibacterial sutures [24] The versatility of this methodenables the modification even in fragile fibers, as the poly(lactic acid),coated with an alloy of Tie6Ale4V through cathodic electrodeposition.The electrodeposition was performed into a glass cell, using graphite an-odes The coated poly(lactic acid) resisted chemical corrosion after 1 weekimmersed in distilled water, while in Ringer’s solution, the coating almostdisappeared [25]

Prevention of spoilage in a uniform layer helps to keep good mance and functionality; therefore, an efficient covering may be achievedthrough electrostatic layer-by-layer deposition This method allows theoption to choose the number of cycles to acquire functional surfaces Thus,this type of materials are composed of alternated positive/negative layersand repeats the process until achieving the desired thickness TheFigure 2.1 Coating in sutures allows the immobilization of bioactive compounds.

perfor-advantages provided by this method are the control of coating morphologyand uniform thickness [26,27].

2.5.2 Grafted sutures

A graft copolymer may be obtained from a matrix polymer and a covalentlybonded monomer in chains (a method called“grafting from”) or directly bythe union of entire chains of polymers onto another polymer (“graftingto”) In both types of functionalization, constituents of the copolymer canpartially retain their identity, and/or possibly thefinal product may acquiredifferent qualities than the polymers by separate According to the polymerstructure, the functionalization of sutures using grafting sometimes requiresactivation with appropriate functional groups to induce reaction with themonomers on a polymer matrix

Grafting can be made through polymerization with acidic or alkalineinitiators, but the integrity of the sutures can be compromised, andtherefore, their functionality Thus, free-radical copolymerization is a morecommon method for suture functionalization Chemical initiators such asperoxides, peracids, azo derivatives, or inorganic compounds are tradi-tionally used in copolymerization via free radicals [28], although thealternative with high-energy radiation presents interesting advantages overchemical methods, specifically for sutures Initiators such as plasma, accel-erated electrons, or gamma radiation can be used The mechanism is based

on the formation of radicals in the backbone polymer, just as the initiator method alternative, but avoiding contamination and thermaltreatment, which could lead to degrading the suture Indeed, the use ofionizing radiation (at an adequate dosage) as a means of sterilization ofsuture materials, has proved high effectivity and efficiency without coun-terproductive effects [29]

chemical-Expanding on the advantages of free-radical grafting in copolymersynthesis, it allows some flexibility concerning the control of reactionvariables, in both homogeneous and heterogeneous systems, since reactionscan be improved by controlling factors such as temperature and reactiontime [30] Regarding the free-radical polymerization mechanism forgrafting (Fig 2.2), this proceeds in a similar way to the generic chain re-action, with steps of initiation, propagation, and termination

In general, hydrophobic grafted copolymers with vinyl monomers andhydrophilic groups, such as NIPAAm, HEMA, and NVIm; yields materialswith enhanced hydrophilic character and potential for a wide variety of

chemical functionalization on the surface including Derivatizations,modifications, immobilizations, or drug loading-releasing systems (Fig 2.3).For example, grafting by preirradiation oxidative method of PP-g-NIPAAm films [31], PP-g-HEMA [32]; and simultaneous irradiation toobtain PP-g-NVIm [33], are affordable options for the functionalization of

“chemically inert” matrix such as PP Investigations regarding PP filmmodifications became the source of inspiration to modify PP sutures andother types of suture polymers

Different factors affect the degree of copolymerization; this is larly true for “grafting from” reactions employing either high-energy ra-diation or chemical initiators It is quite pragmatic to control the degree ofcopolymerization by slight adjusts to the reaction conditions The variablesnecessary to consider in a copolymerization reaction are the concentration

particu-of monomer, solvent, and temperature [34]

2.5.2.1 Monomer

Regarding the grafting of vinyl monomers, their reactivity may be metrically opposite since some monomers easily polymerize, and othersrequire higher amounts of energy to activate the vinyl groups Regarding

dia-Figure 2.2 Grafting via free-radical on inactive surfaces using peroxide groups as initiator.

Figure 2.3 Grafting on PP with highly biocompatible vinyl monomers like NIPAAm, NVIm, and HEMA.

the monomer to be grafted, it must be stable under an air atmosphere andpossess double bonds sufficiently reactive to form covalent bonds with thematrix Alkenes with electron-withdrawing groups are suitable for reacting,e.g., styrene, acrylate, or methacrylate derivatives, being the methacrylateanalogs more adequate to control the chain length via a radical mechanismbecause intermediaries are more energetically stable Also, the radicalpolymerization of N-vinyl monomers as N-vinylcarbazoles, N-vinylindoles,N-vinylpyrrolidones, N-vinylcaprolactams, N-vinylimidazoles, or azoles ingeneral, may be easily controlled, achieving not only a narrow distribution

in chain length but also a defined architecture [35] Then remote groups orheteroatoms contained in the molecule influence the polymerization and itsreaction rate

Besides conventional radical initiators, there are two methods to obtaingrafting employing high-energy radiation; this is through direct irradiationand preirradiation oxidative [36] Preirradiation oxidative is a method withbetter control of reaction variables that requires a matrix able to host orstabilize peroxide and hydroperoxide species on its surface This method isideal when the monomer is prone to homopolymerization Otherwise,when the monomer is low reactive, direct irradiation is maybe the bestoption to achieve the corresponding graft

2.5.2.2 Solvent

Proper selection of solvent for the modification of sutures is perhaps ascrucial as the choice of reactants and materials The solvent must coversome technical aspects follow mentioned Thefirst role of the solvent is todissolve the monomer while the suture is not affected The solvent onlyshould help to swell the suture increasing its reactivity on the surface, butthe solvent should not deform the suture or dissolve it because the me-chanical properties of the products will be affected The second charac-teristic is related to mechanism because some solvents are radical scavengersand, opposite, others are radical generators [37] Also, under ionic mech-anisms, the polarity and ionic strength of solvents are involved in thepolymerization rate, inhibiting or favoring the chain reaction [38] Thethird point to consider for a solvent is the capability to be innocuous and toavoid side reactions that would cause undesirable subproducts, waste, ortoxic residues The last characteristic that must satisfy an ideal solvent is theeasiness of removal, and if it is possible, recycling Moreover, the choice of asolvent must fulfill the normative for the synthesis of medical devices, i.e.,solvents destinated for biomedical devices and sanitary materials are

restricted to those with no toxicity, biodegradable, biocompatible, andnon-halogenated [39].

2.5.2.3 Temperature of reaction

An external stimulus is necessary to start free-radical reactions throughinitiators or peroxy-/hydroperoxy-species formed by ionizing radiation.Usually an increase in temperature or exposure to light provide enoughenergy for homolytic bond cleavage and starts the polymerization process.Higher kinetic energy increases molecular diffusion and the number ofeffective collisions, leading to effective chain growth The temperaturenecessary to break the RO-OR peroxide bonds and RO-OH hydroper-oxides to initiate the chain polymerization reaction is relatively low andshould not exceed the glass transition temperature of the pristine suture Insome cases, is possible to reach initiation energy at room temperature andeven lower [40] Nevertheless, the formation of several active sites needsheat and long reaction times to obtain copolymerization with a high degree

of grafting In some cases, when the grafting is difficult to obtain, due tolow reactivity or interference from the solvent (inhibitor), increasing thetemperature may force reaction to take place, as long as the polymericmatrix and reactants resist heating [41]

2.5.3 Stimuli-responsive polymers on sutures

There are different definitions for stimuli-responsive materials, beyondepistemology, is a fact that all materials in this category share specialproperties, such as when they are exposed to an external stimulus, saidmaterials experiment with physical or chemical changes that produce ameasurable effect Even in the literature, there is more than one word to

define polymers with a response to external stimuli, it is common to findwords like “smart”, “stimuli-responsive”, or “intelligent” to denote thesame kind [42] In any case, the absence of systematization or homogeni-zation in definitions does not impede the exploration and take of benefitsthat these materials bring us

Stimuli-responsive polymers can be classified according to the type ofmaterial, the stimulus to which they respond, and the response to thestimulus Thefirst refers to the structural aspects, for example, in polymers,there are crosslinked structures, interpenetrating networks, hydrogels,

“comb” copolymers, shape-memory polymers, etc The second tion is based on the stimulus to which the materials respond such as tem-perature, pH, light, electricfield, magnetic field, or molecular recognition

classifica-Finally, the third classification is according to the response that the materialshows versus certain stimuli including swelling/collapse, charge, colorchange, physical-state change (solid, liquid, or gas), photoluminescence, orconductivity.

Regarding sutures, it is possible to modify their surface with smartpolymers The polymer chains on the modified sutures are activated whengetting in contact with afluid medium (blood plasma or body fluids), thenchange in the configuration as swelling or collapse take place The degree ofswelling may be controlled by external factors such as pH and/or tem-perature The swelling responsiveness is used in drug-delivery systems tocontrol the release rate of antibiotics, antiinflammatories, or analgesics [43].Interesting investigations have been reported in thefield, for example,the poly(NIPAAm), is a thermo-responsive polymer that in an aqueoussolution has a low critical solution temperature (LCST) of around 32
Cand may reach around 36
C when is modified LCST is a property found

in some thermo-responsive materials that switch their behavior from drophilic to hydrophobic The LCST is a parameter used in the design ofdrug delivery systems The reason is drug loading may be carried out at lowtemperatures, while the release is favored at corporal temperature or slightlyunder it For this reason, poly(NIPAAm) is usually investigated forbiomedical purposes, either as a homopolymer [44] or as a copolymer [45].Also, pH-responsive polymers such as poly(NVIm) are commonly used asbiomedical materials [46] because they combine antimicrobial propertieswith their capability of metal retention and chelation [47]

hy-2.6 Functionalization of nonabsorbable sutures

Nonabsorbable sutures are designed to remain stable for long periods, inboth internal and external suturing Mechanical properties such as resistanceand tensile strength of nonabsorbable sutures are adequate for many types ofprocedures (short or long period) depending on the evolution of thewound Nonabsorbable sutures are utilized to close dermal tissue, whichremoval normally takes 10e14 days, although the time may changedepending on the location and wound environment The use of nonab-sorbable sutures is also destined to remain indefinitely or permanently intissues where wound healing is difficult, or even when the tissue lacks thestrength to remain attached, and is latent the risk of the wound beingexposed again [9]

Expanding on the use of nonabsorbable sutures, these are used in organsand tissues including vital organs for the body’s functioning, for example,the heart and blood vessels, whose rhythmic movement requires the suture

to remain more than 3 weeks [3] Another reason for preferring sorbable sutures is because fluid secretion of certain organs, such as thebladder, causes that absorbable sutures to degrade before the wound healsproperly Sometimes, absorbable sutures induce irritation or inflammation

nonab-in the nonab-intervened zone, provoknonab-ing even biofilm growth, and consequently

an infection In counterpart, nonabsorbable sutures produce a minimalinflammatory reaction in the tissues, usually do not adhere to the tissuessince the body does not recognize them, and maintain the knot correctlyuntil they are removed [48]

Due to the superior mechanical properties of nonabsorbable suturematerials, that is, greater tensile strength and durability, great efforts havebeen made to functionalize them Since many nonabsorbable materials donot show important chemical reactivity, traditional activation methods fortheir functionalization are limited (Fig 2.4), thus its functionalization using

a high energy source, for example, gamma radiation or plasma techniques, isviable [49]

Figure 2.4 Degree of functionalization and bioactivity of suture threads depends on the type and reactivity of chemical groups in the surface.

preirradiation oxidative technique gives PP-g-AN sutures where the servation of the mechanical properties of the original material is pointedout, with a small increase of 5% in its toughness [51] These grafting ma-terials can subsequently be hydrolyzed to obtain an AAc derivative, i.e., aPP-g-AAc suture that shows stability in both neutral and basic pH media.The hydrolysis functionalizes the surface of the suture with carboxylicgroups capable to load/transfer/release tetracycline hydrochloride undercertain environmental conditions The overall process resulted in a suturewith effective antimicrobial properties against in vitro cultures of Escherichiacoli (E coli), Klebsiella pneumonea (K pneumonea), and Staphylococcus aureus (S.aureus) [52,53].

con-Our Laboratory has taken up the line of research on suture threads andhas developed graft materials mediated by gamma radiation with AAc andGMA on PP sutures, for the irreversible immobilization of vancomycinthrough the formation of a covalent bond with the epoxy group of the PP-g-GMA graft In addition, drug release studies were performed with thePP-g-AAc suture, with positive results in adhesion and inhibition tests

in vitro against S aureus [18] These examples consolidate the fundamentalidea of chemical functionalization or loading in suture threads with po-tential antimicrobial activity

2.6.1.1 Functionalization with azoles

Azole-derived heterocycle structures are known to be part of a wide variety

of drugs such as antivirals, antiinflammatories, analgesics, antidepressants,and anticancer, but mainly for being used as antimicrobials [54e56]

If we focus our attention only on antimicrobial activity, azoles are anexcellent option given their inherent biocidal properties [57] As anexample, we have the quaternary salts of butyl-, hexyl- and octyl-imidazolium, which have in vitro activity against E coli, S aureus, B.subtilis, P.fluorescens and S cerevisiae [58] Furthermore, according to recentworks, imidazole oligomers have been shown to eliminate >99.7% of

S aureus and E coli within the first 30 s of contact, simply with the mation of imidazolium bromides [59] Although these polymeric materialsare not yet commercially used in drugs, work is underway to graft theseoligomers into biomaterials for the manufacture of sutures with passiveantibacterial properties, the advantage of which is that they are not invasiveand only act in the contact area [60]

for-A very convenient method for imidazolium group formation is throughthe quaternization of amines with methyl iodide (MeI) When using

iodinated compounds, the activation energy of the reaction is lowercompared with analogous halogenated derivatives (bromides and chlorides)[61,62] In addition, it has the advantage that the N-alkylation reaction can

be carried out in nonpolar solvents and at room temperature The product

of the reaction is an imidazolium iodide derivative that potentiates theantimicrobial activity of the material surface In previous studies, NVIm hadalready been grafted into other medical grade materials such as PVC to laterfunctionalize them with MeI and endow the surface with bacteriostaticactivity [60], so the same methodology was easily transferred to the func-tionalization of NVIm-grafted sutures [63] The advantage is that quater-nization with alkyl iodides can be followed visually with the darkening ofthe suture and quantification can be determined gravimetrically, whereantimicrobial activity has been found to be related to the degree of grafting(Fig 2.3)

With respect to the antimicrobial properties of modified suture threadsafter MeI treatment, in previously grafted PP sutures, it was found that the

progressively depending on the MeI concentration Properly, the zone of

[(PP-g-NIPAAm)-g-NVIm]/MeI in the S aureus strain was greater than in the

E coli strains, where inhibition was moderate [63] These results indicatethat imidazolium is selective to attacking bacteria, which is crucial evidencewhen looking for specific antimicrobial capabilities in modified materials.2.6.1.2 Functionalization with Ag

A different approach to modifying nonabsorbable sutures is through theincorporation of Ag into the surface Studies of the effect of colloidal silver

on bacterial inhibition in S aureus colonies have been quantified positively[64]; also, it is possible tofind several papers towards the therapeutic valueand possible side effects of silver [65] Both Ag(I) and Ag(0) show anti-microbial activity Specially, there are interesting studies when silver nitrate,AgNO3, is used in treatments to combat diseases of viral origin [66] Themost used source to obtain Ag(I) is AgNO3, which possesses an antimi-crobial effect and desirable characteristics such as high solubility and relativebiocompatibility Specific studies conducted on S aureus and E coli revealthat Ag(I) ions kill bacteria thanks to a mechanism that damages themembrane and interferes with metabolic activity at the intracellular level[67] Silver does not necessarily have to be in the solution It is possible toincorporate nanoparticles that destroy the target cell There is still no

consensus on the mechanisms associated with the activity of nanoparticles(cell damage) and their correlation with particle size [68], and still research is

to be made

In the reduction methods, in general, the ionic salts of Ag(I) can bephoto-reduced in a homogeneous aqueous medium using intermediateAg(I) complexes with organic binders [69] In situ chemical reduction ofAg(I) with NaBH4 on porous poly(NVIm) beads have also been recentlyused, resulting in Ag(0) nanoparticles in an acidic medium, with the ability

to control and eliminate S aureus and E coli [70] While in Ag duction, unlike chemical methods, the formation of waste that requiresfurther purification is avoided and large amounts of energy are not required.Photoreduction is carried out in a controlled manner in reactions withpolymers such as polyethylene diamine [71], allowing the formation ofAg(0) nanoparticles, in an eco-friendly way [72], easy, and sustainable [39]

photore-An important mechanism through, which polymer chains reduce Ag,possibly proceeds through the complexation of the Ag salt with the het-eroatoms of the carbonyl groups [73], hydroxyl, amide, or imidazole [74],

as the case may be Such intermediates are formed between the graftedchains or on the surface of the material In a second step; either by theaction of sunlight, thermal heating, the action of a chemical reducer, or acombination; the reduced Ag particles are formed, remaining adhered“on”

or“among” the polymer chains whose noncovalent interactions betweenthe metal and polymer are strong enough to remain as a unit in the suturefilament

In recent years, a string of articles on Ag suture functionalization hasshown different angles of the same principle about loading orfixing metal

on the biomaterial surface Adhesion is facilitated if the suture surface meetsone or more of the following properties: high surface area (high porosity),high density of reactive functional groups on the surface, and swellingcapacity Some more representative examples are mentioned in thefollowing paragraphs

Modification of PP sutures with vinyl monomers was discussed inprevious sections, but we will delve into some investigations In a studycarried out by our working group, graft copolymers of PP-g-HEMA-g-NVIm, PP-g-NIPAAm-g-NVIm, and PP-g-NVIm were compared; all ofthem loaded with Ag(0) by photoreduction with natural light [75] Theloading with Ag was made using aqueous solutions of different concen-trations of AgNO3 (10-10,000 mg L1) and under environmental condi-tions around (25
C), which meant an advance in the methodology, since

heating and the use of reducing agents such as sodium citrate or thiosulfitewere avoided For the reduction to be effective, the suture must be able toswell in an aqueous medium, which guarantees maximum absorption of

Agþ ions between the chains Swelling occurs within thefirst 4 h, cally reaching the limit after 24 h of reaction The experiments showed thatmore concentrated solutions and with higher percentages of swelling inwater loaded more Ag In addition, by comparison, the pristine PP sutures,

practi-as well practi-as the grafted PP monofilaments were subjected to treatment withAgNO3and were prepared for the in vitro bioactivity tests against S aureusand E coli strains The results showed that the pristine PP positive controlsdid not inhibit the bacteria growth since the PP surfaces have practically nochemical reactivity and were not capable of loading Ag; while the graftedsuture threads treated with AgNO3showed an outstanding ability to inhibitmicrobial growth after 24 h

Inhibition patterns also provide us with interesting information HEMA)-g-NVIm/Ag was found to produce inhibition halos from con-centrations as low as 10 mg L1, and showed an increase in the zone ofinhibition consistently to 1000 mg L1 to then remain constant up to10,000 mg L1 On the other hand, the grafted copolymer [(PP-g-

Another important fact is that Ag particles are more effective in S aureus(Gram-positive) cultures compared to E coli (Gram-negative) cultures Thiswas due to the fact that the S aureus strains were more susceptible to lowconcentrations of Ag for the two grafts analyzed when an increase in theinhibition halo was observed consistently up to 10,000 mg L1 (8 mm);while in cultures with E coli, only the maximum inhibition zone of 5 mmwas obtained [75] The results indicate that the activity of the Ag particles issubject to both, the graft percentages, the type of polymer graft, and theamount of metal adhered to the surface The BALB/3T3 cell lines weretested with the same sutures used to determine the inhibitory capacity, that

is, with [(PP-g-HEMA)-g-NVIm (36/22%)]/Ag and NVIm (20/22%)]/Ag Thanks to the WST-1 assays, cytocompatibility wasdetermined to be acceptable after 24 h of incubation, in addition, greatercell survival was observed with the material [(PP-g-HEMA)-g-NVIm (36/22%)]/Ag, which implies that PHEMA is a highly biocompatible polymer

[(PP-g-NIPAAm)-g-2.6.2 Modified silk sutures

Silk suture is a special case, this type is a braided multifilament coated withbeeswax It is a natural polymeric suture made from long-lasting fiberproteins, for this reason, it can be considered nonabsorbable, although after

1 year it loses tensile strength and suffers degradation, according to reportsfrom in vivo studies [76] The reason to modify silk sutures lies in their greatflexibility and maneuverability as well as tying strength In fact, silk fibershave been modified at a structural level to accelerate their biodegradation as

in the work by Jo et al where 4-hexylresorcinol was incorporated into silkfibers 4-Hexylresorcinol fulfilled a double function, first to promoteproteolysis and second as an antiseptic to inhibit bacterial growth [77]

In silk fibers, as with other sutures, there is a risk of bacterial growth This is the reason why, in 2020, Baygar carried out the modifi-cation of silk sutures through the application of a coating with propolis [78],taking advantage of the fact that silk contains eCO- and eNH- groups,propolis can efficiently adhere to the surface Once the coating was done,the loading was carried out with Ag nanoparticles of biogenic origin Theresults indicated the synthesis of a functional and broad-spectrum antibac-terial capacity suture

over-In summary, of the different methods for functionalization of sorbable sutures, the Ag inclusion technique on the surface is presented asthe alternative with the greatest projection thanks to its biocompatibility,flexibility and inhibition capacity under different chemical environments, inaddition to high yields in metal loading and ease of obtaining

nonab-2.7 Functionalization of absorbable sutures

Absorbable sutures are composed of materials assimilable by organic tissuesand are digested by proteolytic enzymes or hydrolyzed by tissuefluids after

a certain time of exposure, examples of sutures with these characteristics areCatgut Simple, Chromic Catgut, Vicryl, PDS, Dexon, Maxon, ResorbaPGA, etc

Unlike non-absorbable sutures, equipping suture threads with crobial properties is an idea already grounded in commercial absorbablethreads For example, polyglycolic acid sutures (merchandised under thename Vicryl from Ethicon) have been coated with Ag nanoparticles [79].Using proven and available antibiotics in commercial sutures seems themost intuitive and feasible way to modify sutures Modifications can bedesigned according to a certain release profile, but in general, it is desirablethat the diffusion of antibiotics reach maximum effectiveness at least 2 daysafter the application There are already reports about modifications withtriclosan (a powerful antibacterial and fungicide) for the functionalization ofabsorbable sutures with positive results, so it is plausible to think that in the

antimi-future more of these antibiotic/suture combinations will become morecommon [80,81].

2.7.1 Functionalization with silver

In Gallo 2016 work, Ag clusters were deposited on Coated VICRYL

multifilament-like sutures were tested in bacterial cultures of S aureus and

E coli, inhibiting both even after 21 days The Ag particles act throughsuture degradation-controlled release mechanisms, where half of the Agload is released within the first 7 days It is worth mentioning that thesutures were tested before and after the Ag was added and that the usefullife of the suture (preprogrammed) does not seem to be significantlyaffected In fact, in the degradation kinetics experiment, physiologicalconditions were simulated with phosphate buffer solutions at pH 7.4 for

4 weeks, it seems that the degradation of the suture helps to the diffusion ofthe Ag particles and, therefore, inhibits any bacterial activity Regarding thefunctionality, stability, and duration of the suture threads, microscopic andelemental analyzes show that there is uniformity in Ag deposition along thesurface The MTT cytotoxicity results support the conclusion that thesetypes of sutures are suitable for use in the closure of certain types of wounds.Two years later in 2018 Gallo and his collaborators used the same type

of absorbable suture as Polyglactin 910 to improve Ag adherence butpreviously coated it with silk sericin [83] The sutures were activated in abasic medium with sodium hydroxide, in this way, the adhesion of the silksericin is promoted, to load the Ag by dipping it in a AgNO3solution in alater step The sutures were tested in the presence of strains of S aureus and

E coli, showing inhibition in microbial proliferation for up to 21 days

2.7.2 Chitin sutures

An entirely organic alternative to absorbable sutures is to use sutures madefrom chitin fibers Chitin is a glucose derivative present in arthropodexoskeletons and some crustaceans and mollusks Its linear structure allowsfibrous structures to be built, with adequate resistance for absorbable su-tures Prolonged exposure to tissues does not produce adverse reactions or

at least is minimal, allowing an appropriate environment for healing.Compared to other sutures such as catgut and Dexon, chitin retains itsmechanical properties (tensile strength, Young modulus, andflexibility) forlonger days [84]

The development of more and better chitin sutures has been enhancedthanks to research focused on improving the physical properties of thematerial It is possible to reinforce the fibers by doping with cellulosenanocrystals of bacterial origin [85] The nano cellulose is added to thechitin powder together with a solution of urea and NaOH In a secondprocess, the solution is subjected to a“wet-spinning” process to interweavethe fibers that constitute the suture threads [86] The advantage of thesesutures is that they are fully biodegradable, biocompatible, and promote cellregeneration, this helps to accelerate wound healing, demonstrating that anantibiotic is not necessary to reduce the risk of infection.

2.7.3 Caprolactam sutures gentamicin/silver loaded

As we have already noticed, absorbable sutures can be loaded with acommercial antibiotic or Ag, but also with a combination of both types ofantimicrobials, such as caprolactam sutures that were built in one step fromthe polymer (beads) and mixing them with dispersed Ag and a solution ofgentamicin The mixture was treated by electrospinning using a“spinneret”and applying a voltage of 12 kV Once the fibers of different gauges(3e12 mm width) were obtained, they were wound into multifilament ofdifferent diameters

The sutures are sterilized and subjected to biocompatibility tests withHaCaT cell lines with acceptable results to be used as medical healingdevices As for the antibacterial activity, this was performed with colonies ofPseudomonas aeruginosa, and it was observed that the combination of drugsactually helps, also in the wound healing tests, there is no healing inter-ference with respect to the control sutures

2.7.4 Drug-loading on absorbable sutures

In addition to antibiotics, absorbable sutures can also be loaded withantiinflammatory drugs The reason for adding this type of drug in suturematerials is justified based on the prevention of possible damage caused bysome tissue reaction, since, as mentioned, combined factors such as thenature of the material and exposure to tissue can cause a response by theimmune system in the presence of a foreign body There are reportedworks where vicryl absorbable sutures are modified, which basically consists

of a copolymer composite of PLGA with diclofenac [87] In this work,diclofenac was loaded directly into a mixture of dichloromethane andN-N-dimethylformamide (DMF), the mixture was impregnated through

electrospray The release of diclofenac was monitored through UV-Vis andthe results indicate that more than 50% of the drug is released within thefirst 48 h and continues to release until day 10 In the same way as withother sutures, by modifying them with nonaggressive reaction methods andconditions, the mechanical properties of the sutures are not affected and arefunctional.

2.8 Conclusions

Modifying the structures and surfaces of the suture threads is a reliable andpractical way to develop biomedical materials with enhanced or tailor-madeproperties Whether in absorbable or nonabsorbable sutures, it is possible tomake superficial modifications by various methods, which helps in thehealing process and, consequently, the patient recovery The methods forsuperficial modifications can be categorized into two main groups, chemical(such as grafts, derivatizations, and complexations) and physical (such ascoatings, loading, and doping) Surface modification of sutures is a novelfield in constant change and improvement The search continues so that theoperation of the original materials does not appreciably change and improvethe healing Furthermore, and in accordance with what is explained in thischapter, it can be concluded that the functionalization of sutures withantimicrobial properties is affordable The main objective is to get saferdevices for the postoperative healing process

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