Selection and Application of Synthetic Polymeric Materials In

SELECTION AND APPLICATION OF SYNTHETIC POLYMERIC MATERIALS IN

SURGICAL SUTURES

KENNETH BRANSON SIMMONS

(Under the Direction of Jason Locklin)

ABSTRACT

Wound closure is a complex process that relies on a variety of tools and materials to produce the best outcome for patients. The use of a single suture for the closure of all fascia is ill advised and should be avoided. This thesis seeks to inform the reader of the characteristics and utility of various synthetic polymeric materials and their application as surgical sutures.

INDEX WORDS: Surgical Sutures, Synthetic, Absorbable, Nonabsorbable SELECTION AND APPLICATION OF SYNTHETIC POLYMERIC MATERIALS IN

SURGICAL SUTURES

KENNETH BRANSON SIMMONS

B.S., The University of Georgia, 2012

A Thesis Submitted to the Graduate Faculty of The University of Georgia in Partial

Fulfillment of the Requirements for the Degree

MASTER OF SCIENCE

ATHENS, GEORGIA

Kenneth Branson Simmons

SURGICAL SUTURES

KENNETH BRANSON SIMMONS

Major Professor: Jason Locklin Committee: Jonathan Amster Jeffrey Urbauer

Electronic Version Approved:

Suzanne Barbour

Dean of the Graduate School

The University of Georgia

August 2017 iv

DEDICATION

To my father, Kenneth Simmons, who taught me the importance of an education.

To my fiancée, Laura Anne Cotney, for bringing music to my life and helping me to keep my wits about me. v

ACKNOWLEDGEMENTS

I would like to acknowledge the support and guidance given by my major professor, Dr. Jason Locklin, for his guidance and support in my graduate studies.

Additionally, I would like to acknowledge all members of the Locklin group for their input and support during group meetings, literature talks, and seminar.

I would like to thank my committee members, Dr. Jonathan Amster and Dr.

Jeffrey Urbauer, for their support.

Finally, I would like to thank my employer, Ethicon – A Johnson & Johnson

Company, for providing funding throughout my studies. vi

TABLE OF CONTENTS

Page

ACKNOWLEDGEMENTS………………………………………………………………………………v

CHAPTER

1 INTRODUCTION ………………………………………………………………………………………1

Absorbable vs Non-Absorbable Suture ………………………………………………………. 2

Monofilament vs Multifilament Suture ………………………………………………………… 3

Coated vs Non-Coated Suture ………………………………………………………………… 4

Suture Sizes……………………………………………………………………………………... 4

2 MONOMERS ……………………………………………………………………………………………5

Lactide …………………………………………………………………………………………….5

Glycolide ………………………………………………………………………………………….6

p-Dioxanone ……………………………………………………………………………………...7

Trimethylene Carbonate ……………………………………………………………………...... 8

ε-Caprolactone ………………………………………………………………………………...... 9

3 HOMOPOLYMERS .…………………………………………………………………………………. 10

Polyglycolide ……………………………………………………………………………………10

Polylactide ………………………………………………………………………………………11

Poly(p-dioxanone) ……………………………………………………………………………...12

Poly(4-hydroxybutyrate) ……………………………………………………………………….12

4 COPOLYMERS OF TWO MONOMERS …………………………………………………………...14

Poly(glycolide-co-lactide) ……………………………………………………………………...14

Poly(p-dioxanone-co-glycolide) ……………………………………………………………… 16

Poly(p-dioxanone-co-trimethylene carbonate) ……………………………………………...16 vii

Poly(glycolide-co-trimethylene carbonate) …..……………………………………………... 16

Poly(glycolide-co-ε-caprolactone) …………………………………………………………… 17

Poly(lactide-co-ε-caprolactone) ……………………………………………………………… 18

5 COPOLYMERS OF THREE MONOMERS …………………………………………………………19

Poly(glycolide-co-trimethylene carbonate-co-ε-caprolactone) …………………………….19

Poly(glycolide-co-trimethylene carbonate-co-p-dioxanone) ……………………………….19

Poly(ε-caprolactone-co-trimethylene carbonate-co-p-dioxanone) ……………………….. 20

6 COPOLYMERS OF FOUR MONOMERS …………………………………………………………. 22

Poly(glycolide-co-L-lactide-co-trimethylene carbonate-co-ε-caprolactone) ……………...22

7 NONABSORBABLE SUTURE ……………………………………………………………………....23

Polyamides …………………………………………………………………………………….. 23

Polyesters ……………………………………………………………………………………… 24

Poly(vinylidene fluorides) …………………………………………………………………….. 25

Poly(tetrafluoroethylene) ………………………………………………………………………26

Polyolefins ………………………………………………………………………………………27

Ultra-high molecular weight polyethylene ……………………………………………………28

8 FUTURE DIRECTIONS ………………………………………………………………………………30

Barbed Suture …………………………………………………………………………………..30

Poly(propylene oxide) Suture …………………………………………………………………30

Diacetyl Chitin Coated Suture …………………………………………………………………31

Antibiotic Eluting Suture ……………………………………………………………………….31

Amino Acid Based Nanogel Conjugated Suture …………………………………………….32

REFERENCES ………………………………………………………………………………………….33 1

Introduction: Needles wrought from bone, tendons of a kangaroo, lining of a cow’s stomach.

Despite the macabre sounding nature of this list, as if they are the components of some witch’s brew, these items help to illustrate the history of surgery and surgical suture.

From the first eyed needles, approximately 50,000 years ago1, to the use of kangaroo tendons and bovine serosa as wound closure materials, surgery has employed a wide array of materials to facilitate wound approximation and promote healing. Currently, the field relies heavily on synthetic materials as replacements to these seemingly antiquated, naturally occurring materials. Wound closure requires numerous materials of varying composition and geometry dependent upon the location and nature of the surgery. To rely solely on one type of suture would result in decreased quality of care and increased complications. For this reason, a wide array of wound management solutions are currently available. The intent of this review is to highlight and differentiate the options that are currently available to physicians, and to provide a prospectus on future suture materials. As with any review, this work draws on information from previous reviews2-8 of available materials and seeks to provide an update on the current state of available biomaterials.

A suture is a strand or fiber used to sew parts of the living body9. Given the broad nature of the definition, it is natural that many differing types of suture exist. While many sutures are made from natural materials (silk and catgut), this review will focus mainly on synthetic materials. The ubiquitous nature of surgery ensures the 2 large size of the market for surgical suture. The market for surgical suture in 2016 exceeded $3.46 billion, and is expected to reach $4.40 billion by 202110. During this time, expected growth is 5% per year, due to an increase in the number of surgeries and the launch of new suture materials10.

In order to discuss the varying synthetic sutures, the types will be bifurcated into absorbable and nonabsorbable. The composition, geometry, and utility of each suture family will be discussed to act as a useful reference for those seeking to compare the characteristics of different suture materials. This will include features such as size, color, and any specialized features used to distinguish the suture. In addition to the distinction between absorbable and nonabsorbable suture, a distinction also exists between braided and monofilament suture. This will be included in the discussion of each suture material.

Absorbable vs Non-Absorbable Suture:

The choice between an absorbable and nonabsorbable suture depends largely on the amount of time required for proper wound healing, whether the suture will need to be removed, and the location of the tissue approximation.

Absorbable suture is designed to be implanted into the body and degrade over time without the need for later removal. These suture materials are designed to be susceptible to hydrolysis and enzymatic attack within the body and to exhibit a certain tensile strength profile at given times post implantation. Absorbable sutures are manufactured using materials that are easily metabolized by the body and that do not produce hazardous byproducts. In general, absorbable sutures are used for the approximation of fascia within the body where tensile strength is required for a period 3 between a few days and several months. Synthetic polyesters are most often employed for absorbable sutures, but natural products like catgut can also be used.

Non-absorbable sutures are manufactured using materials that will not degrade when implanted into the body. Rather, they become encased in the tissue as the wound heals and are left in place. For this reason, they must be manufactured from materials that will not cause adverse reaction. Polypropylene, nylon, and silk are common materials used for the manufacture of nonabsorbable suture. Nonabsorbable sutures can be used for surface approximations or internal wound closure where an extended healing time is required. This type of suture is often used for cardiovascular and neurological surgeries, external wound closure, wound closure within the body cavity, and for prosthesis attachment11.

Monofilament vs Multifilament Suture:

Sutures can be divided into monofilament and multifilament or braided sutures. Monofilament sutures are composed of a single strand of material and are often uncoated and nonabsorbable. Since they are monofilament, they tend to invoke less of an inflammatory response than braided suture due to the reduced surface area of the suture. While they move through tissue more easily than braided suture, they do suffer from poorer handling characteristics. Monofilament suture typically requires more knots to ensure secure placement and maintain memory when removed from packaging.

Multifilament sutures are composed of numerous monofilament strands that are braided together. Braided sutures are often coated and absorbable. The increased surface area does increase the change of infection and makes for more difficult 4 passage through tissue. For this reason, they are often coated with a material to provide a more homogeneous surface. Braided sutures are stronger than monofilament sutures of the same size, have reduced package memory, and have improved knot security12.

Coated vs Non-Coated Suture:

The addition of a coating material to a suture can be a vital part of ensuring consistent performance and improving handling. Typically, a coating is added to a braided suture to improve passage through tissue and to reduce the surface area available for infection. Coatings can also be used to introduce antimicrobials, like triclosan13 and chlorhexidine gluconate14, onto the suture to provide a zone of inhibition. Common coatings used include calcium stearate, wax, PTFE, silicone, as well as a multitude of copolymers7.

Suture sizes:

The size of a suture is the measure of the diameter of either a monofilament or braided suture, and can be classified in either metric or USP (United States Pharmacopoeia) sizes. In the USP sizing system, absorbable sutures range from size 10-0, the smallest, to size 4, the largest15. In the metric sizing system, absorbable sutures range from size

0.2, the same as USP 10-0, to size 6, the same as USP size 4. Nonabsorbable sutures also conform to these size conventions, but have a larger range. In the USP sizing system, nonabsorbable sutures range from size 12-0, metric size 0.01, to size 10, metric size 1216. For the determination of these sizes, a minimum of 10 strands must be measured for diameter, as discussed in USP <861>17. 5

Monomers: As with any polymer, consideration must be given to the monomers used to produce a final product. Currently, five monomers have obtained FDA clearance for use in synthetic absorbable sutures. The approved monomers are glycolide, lactide, p- dioxanone, trimethylene carbonate, and ε-caprolactone.

Lactide:

Lactide ((3S,6S)-3,6-dimethyl-1,4-dioxane-2,5-dione) is formed by the dimerization of lactic acid. Polymerization from the dimer is required since direct reaction of lactic acid results in a low molecular weight polymer18. This low molecular weight product can be used to produce lactide through the addition of heat and vacuum. Due to the presence of a chiral center, lactide exists in both the d and l conformations, resulting in a variety of polymerization possibilities19. The naturally occurring l isomer is used in the homopolymer PLLA, while a mixture of the d and l isomers is used for PDLLA. The homopolymer PDLA has a higher crystallinity than PLA, but does not have any current applications in the field of surgical suture. Synthesis of poly(lactic acid) is most frequently achieved through the ring opening polymerization of lactide in the presence of a stannous octoate catalyst20. While stannous octoate is the most common catalyst, 6 other metal catalysts like zinc powder and aluminum isopropoxide, have been demonstrated to be effective for the polymerization of PLA21.

Glycolide:

Glycolide (1,4-Dioxane-2,5-dione) is formed by the dimerization of glycolic acid and has found utility as one of the most common monomers in the field of synthetic absorbable sutures. The direct polymerization of glycolic acid, the simplest α-hydroxy acid, is not suitable to make high molecular weight polymers7. Condensation of the monomer is a reversible reaction that is susceptible to hydrolysis based depolymerization. Therefore, the cyclic dimer, made by heating low molecular weight polyglycolic acid under reduced pressure, is used in place of glycolic acid22. Glycolide is heated in the presence of a catalyst to initiate a ring opening polymerization. Typical catalysts include stannous octoate (tin(II)-ethylhexanoate), zinc nitrate, antimony trioxide, or antimony trihalides23. Stannous octoate is the most commonly used catalyst as this material has received FDA approval as a catalyst for use with resins intended for contact with food24. The content of glycolide is manipulated for most polymers used in the production of suture. With a few exceptions, glycolide comprises the bulk of the backbone content for suture. Glycolide, along with lactide, are often referred to as the hard, or rigid, parts of the polymer backbone due to reduced freedom of motion compared to monomers like p-dioxanone or ε-caprolactone7. 7 p-Dioxanone:

p-Dioxanone, sometimes referred to as PDO, is the common name given to 1,4-dioxan-

2-one. Traditional preparation of PDO consisted of the reaction of monosodium salt of ethylene glycol with chloroacetic acid under inert atmosphere. Conversion of the starting material to sodium hydroxyethoxyacetate is achieved, followed the formation of the free hydroxy acid in the presence of HCl. A crude product is achieved by precipitation in ethanol followed by filtration. Multiple recrystallizations and distillations are then conducted to achieve a purified product. This synthetic route was used for the manufacture of PDO monomer for many years, until a more efficient pathway was proposed. The alternative, and more widely used, synthetic route relies on the dehydrogenation of diethylene glycol in the presence of a copper chromite catalyst at elevated temperature. The reaction product is dried over molecular sieves and vacuum filtered. Benzyl bromide and pyridine are added and the reaction mixture is distilled under reduced pressure before being added to excess ethyl acetate. The solution is cooled to -20°C and seed crystals are added before the mixture is further cooled to -

34°C. Additional filtrations and recrystallizations are conducted to achieve a final purified product8. 8

Trimethylene Carbonate:

Trimethylene carbonate (1,3-dioxan-2-one), sometimes referred to as TMC, is an FDA approved monomer for suture products used in the manufacture of Caprosyn, Monosyn,

Biosyn, Maxon, and Maxon CV. TMC undergoes spontaneous polymerization at temperatures above 100°C, and can be synthesized from either 1,3-propanediol and ethyl chloroformate or oxetane and carbon dioxide in the presence of VO(acac)2 catalyst. Although TMC is capable of undergoing ring opening polymerization to form poly(trimethylene carbonate), PTMC, the polymer has low mechanical strength and is not suitable as a suture material25. Therefore, TMC is coupled with glycolide and other approved monomer to form multiblock copolymers26. 9

ε-Caprolactone:

ε-Caprolactone, often referred to simply as Caprolactone, is the seven-membered cyclic lactone of caproic acid. This monomer is commercially synthesized from cyclohexanone via the Baeyer-Villiger oxidation, a common technique for conversion of cyclic ketones to lactones27. Much like TMC, caprolactone is capable of undergoing ring-opening polymerization to create poly(caprolactone), PCL. However, much like

PTMC, the PCL homopolymer does not possess favorable characteristics for use as a suture material. In the case of PCL, the drawback is that degradation occurs on the order of years28. To increase the degradation rate, caprolactone is added to other monomers to produce multiblock polymers suitable for use as suture26. 10

Homopolymers: Polyglycolide:

The first synthetic absorbable suture, polyglycolic acid (PGA), was first marketed in

1970 under the name Dexon by Davis and Geck29. While Dexon is still on the market, it is now a product of Covidien. Dexon is offered in both monofilament and braided, coated and uncoated, as well as undyed or dyed (green). The uncoated version, Dexon

S30, is offered in addition to a suture coated with a copolymer of poly(oxyethylene oxypropylene), Dexon Plus, and a suture coated with polycaprolate, Dexon II31. PGA sutures is available as a braided suture in sizes 8-0 to 2 and as a monofilament suture in sizes 10-0 to 8-0. For size 6-0 or larger, PGA retains approximately 65% of its tensile strength at two weeks post implantation and 35% at three weeks post implantation. For size 7-0 or smaller, PGA retains approximately 55% of its tensile strength at two weeks post implantation and 20% at three weeks post implantation{Covidien, #109}. There are other PGA sutures on the market under the trade names Petcryl32 (Dolphin

Sutures), Visorb33 (CP Medical), Truglyde34 (Sutures India), Safil35 (B. Braun AG), PGA

Resorba36 (Resorba). Ethicon has recently received 510(k) approval for a PGA suture under the trade name Pliasure37.

PGA offered an alternative to catgut in that it had a known degradation profile. Since the introduction of polyglycolide suture, it has found significant use for short term wound closure. While PGA offers a high initial tensile strength, it is found to lose approximately 50% of its strength after two weeks, and 100% after a period of four 11 weeks. The material is completely degraded within four to six months after implantation. As with most synthetic absorbable sutures, PGA is synthesized through a ring opening polymerization of glycolide in the presence of an organometallic catalyst. Common catalysts include stannous chloride and trialkyl aluminum. This method of polymerization can produce a product with a MW between 20 and 140 kDa6. Products within this range are suitable for extrusion into suture material. Dexon, the most prominent polyglycolide suture, is manufactured through melt spinning of PGA chips, followed by elongation, annealing, and treatment in a vacuum oven6. Due to the highly crystalline nature of PGA, this suture is often produced as a braided multifilament suture, or as a very small monofilament suture. Sterilization of PGA is achieved through the use of ethylene oxide gas, as exposure to gamma radiation has been shown to decrease the tensile strength of the final product38.

Polylactide:

Although PLA shares a similar structural backbone to PGA, the properties of the polymer are markedly different. There are no sutures currently marketed using PDLA or

PLDLA. The only 100% PLLA suture to receive FDA approval is Orthodek, manufactured by Teleflex39. Due to a much longer absorption time (5.6 years),

Orthodek is intended for soft tissue ligation in which extended approximation is required, such as ligament or tendon repair7. Orthodek was approved for use in size 2 (metric size 5) as an undyed, braided, and coated suture. Little information is available regarding this product, and the status of the trademark for Orthodek is listed as

“continued use not filed within grace period, un-revivable” since 12/26/201440.

Poly(p-dioxanone):

Synthesis of poly(p-dioxanone), often referred to as PDS, PPDO, or PDO, is achieved through the ring opening of the highly purified monomer 1,4-dioxan-2-one. The introduction of PDS suture by Ethicon offered the first large size (2-0 and larger) monofilament absorbable suture. PDS offered an alternative to Vicryl and Dexon for the suturing of fascia, since it can retain its tensile strength for six weeks, instead of the three to four weeks for Vicryl. As a monofilament suture, PDS offers reduced drag compared to a braided suture, and provokes less tissue inflammation. In 1982, an advancement was made to the production of PDS, with the introduction of PDSII. While chemically identical, the suture is annealed above the melting temperature, softening the exterior of the suture and improving the flexibility of the final product.

PDS is available as a monofilament suture in USP sizes 7-0 through 2. For size

3-0 or larger, PDS retains approximately 80% of its tensile strength at two weeks post implantation and 60% at six weeks post implantation. For size 4-0 or smaller, PDS retains approximately 60% of its tensile strength at two weeks post implantation and

35% at six weeks post implantation{Ethicon, 2017 #119}. It can be purchased undyed or dyed with D&C Violet #241. Polydioxanone is marketed under the names PDS II41

(Ethicon), PDS Plus42 (Ethicon), MonoPlus43 (Aesculap), Monodek44 (Teleflex),

Surusynth45 (Suru International), DemeDIOX46 (DemeTech), and Duracryl47

(Dolphin). Sterilization of polydioxanone is achieved using ethylene oxide gas41.

Poly(4-hydroxybutyrate):

Poly(4-hydroxybutyrate), or P4HB, is a special polymer used for the manufacture of surgical suture in that it is not manufactured through ring opening polymerization of any 13 of the traditional monomers. Rather, P4HB is produced by microorganisms through the polymerization of hydroxybutyryl-CoA in situ48. P4HB suture has been approved for use by the FDA and is marketed under the names TephaFLEX49 (Tepha, Inc.) and

MonoMax50 (Aesculap). P4HB suture is available in sizes 5-0 to 2 and maintains approximately 50% of its initial tensile strength after 30 weeks. Degradation is complete between 12 and 18 months post implantation{Tepha, #160}. Sterilization of P4HB is achieved through the use of ethylene oxide gas, as exposure to gamma radiation has been shown to decrease the molecular weight of the final product48. 14

Copolymers of 2 monomers: In many cases, the properties of a homopolymer suture are not suited to the needs of the surgeon, or the tensile strength of the tissue. For this reason, several polymers are used that have multiple components in the polymer backbone. This section focuses on the use of di-block polymers, the most populous group, for the manufacture of suture.

Poly(glycolide-co-lactide):

Poly(glycolide-co-lactide), also known as PLGA or polyglactin, is a class of copolymers used in the medical device industry. By varying the mole percent of each monomer, it is possible to tune the physical characteristics of the final polymer. The most common mole ratio used in this copolymer class is 90% glycolide to 10% lactide, also known as polyglactin 910. Polyglactin 910 was first introduced in 1974 under the name Vicryl

(Ethicon), and offered an alternative to the rapid degradation of PGA suture29. While most polyglactin 910 suture is braided, several small monofilament sizes (10-0 and 9-0) are available. Monofilament Polyglactin 910 retains approximately 75% of its tensile strength at two weeks post implantation and 25% at four weeks post implantation.

Braided polyglactin 910 is available in USP sizes 8-0 through 3, and is available undyed or dyed with D&C Violet #2. Braided Polyglactin 910 retains approximately 75% of its tensile strength at two weeks post implantation and 40% at three weeks post implantation. Absorption of both monofilament and braided polyglactin 910 is complete between 56 and 70 days post implantation. For the Vicryl product line, to reduce drag through tissue, the multifilament sutures are coated with a mixture of equal parts 15 polyglactin 370 and calcium stearate11. Polyglactin 370 is another copolymer consisting of 65% lactide and 35% glycolide51. This same coating copolymer is also used for

Petcryl 910 and Trusynth. Polyglactin 910 is marketed under the names Vicryl52

(Ethicon), Petcryl 91032 (Dolphin), DemeCRYL53 (DemeTech), and Trusynth54 (Sutures

India). Sterilization of PG910 is achieved using ethylene oxide gas4.

Vicryl Rapide (Ethicon) is a version of Vicryl that has been gamma irradiated to increase the rate of absorption, while still offering the same initial tensile strength55. Vicryl Rapide loses all tensile strength after 14 days56, as compared to untreated Vicryl, which maintains some tensile strength after 4 weeks. Similar products are offered under the names DemeQUICK57 (DemeTech), Petcryl 910 Fast58 (Dolphin), and Trusynth Fast59 (Sutures India). Sterilization is achieved with ethylene oxide gas.

Vicryl Plus60 (Ethicon) is another available suture that differs from both Vicryl and

Vicryl Rapide in that Irgacare MP, a purified form of Triclosan, is also coated onto the surface of the suture to provide an antibiotic barrier during wound healing. A similar product is marketed under the names Trusynth Plus61 (Sutures India). Dolphin Sutures offers an alternative antibacterial polyglactin 910 suture known as Petcryl CS62. The coating of Petcryl CS replaces the antibacterial Triclosan with the antibacterial chlorhexidine. Polysorb63 (Covidien) should also be mentioned at this point, as it is a polyglactin composed of 93% glycolide and 7% lactide. Like other polyglactin 910 sutures, Polysorb is a multifilament suture that available either undyed or dyed with

D&C Violet #2. However, unlike other polyglactin sutures, the coating is composed of a poly(ε-caprolactone-co-glycolide) and calcium stearoyl lactylate. Sterilization is achieved using ethylene oxide gas. 16

In addition to polyglactin 910 and polyglactin 370, there was another member of the polyglactin portfolio of suture, Panacryl. By essentially inverting the monomer ratios of polyglactin 910, Panacryl, which is 95% lactide and 5% glycolide, was capable of maintaining 60% of its strength after a period of 6 months7. Panacryl was an undyed, braided suture, coated in a copolymer of 90% ε-caprolactone and 10% glycolide. It was first approved by the FDA in 199664 and offered the longest lasting absorbable suture on the market. However, due to a number of complications, the product was recalled and pulled from the market in 200665. It was discovered that a number of patients were experiencing adverse effects to the suture material and that their bodies were rejecting it as a foreign body.

Poly(p-dioxanone-co-glycolide):

Poly(p-dioxanone-co-glycolide), or PDG, is a copolymer that is not currently marketed as a suture material. In 2015, a patent was filed by Ethicon for the invention of a PDG copolymer comprised of 92% p-dioxanone and 8% glycolide66.

Poly(p-dioxanone-co-trimethylene carbonate):

Poly(p-dioxanone-co-trimethylene carbonate), is a copolymer that is not currently marketed as a suture material. Some work has been performed to evaluate its suitability as a drug delivery system67, but there no current patents for the use of this material in suture.

Poly(glycolide-co-trimethylene carbonate):

Poly(glycolide-co-trimethylene carbonate), also known as PGTMC or polyglyconate, is a copolymer used exclusively by Covidien for the Maxon suture line68. This copolymer has a molar ratio of 64% glycolide to 36% TMC7. Maxon is an uncoated monofilament

17 suture and is available undyed or dyed with D&C Green #6 and maintain 50% of their tensile strength at four weeks post implantation. Maxon suture is available in USP sizes

7-0 through 169. In addition to Maxon, a version of the suture is approved for pediatric cardiovascular surgery, Maxon CV. Like Maxon, this suture is an uncoated monofilament suture. However, Maxon CV is only available in USP sizes 7-0 through 4-

0 and is dyed with D&C Green #668. Sterilization of Maxon is achieved through the use of ethylene oxide gas70.

Poly(glycolide-co-ε-caprolactone):

Poly(glycolide-co-ε-caprolactone), also known as PGCL or poliglecaprone 25, is a segmented block copolymer comprised of 75% glycolide and 25% ε- caprolactone. Poliglecaprone 25 is a monofilament suture and is available undyed or dyed with D&C Violet #2. PGCL is available in USP sizes 6-0 through 1. The key aspect that sets PGCL apart is improved pliability over other monofilament sutures, such as PDS. This is achieved through the synthesis of a prepolymer of caprolactone and glycolide, to produce a soft polymer chain. This prepolymer does not have the same monomer composition as the final product. Therefore, more glycolide is then added to the prepolymer, incorporating hard segments to the polymer chain4. This improves the physical characteristics of the final product, allowing for high tensile strength while incorporating improved pliability71. The undyed suture has a high initial tensile strength that degrades to 50-60% of its initial strength after one week, and 20-

30% after two weeks. The dyed suture has a slightly slower degradation profile with 60-

70% of its initial strength remaining after one week and 30-40% remaining after two weeks. Complete hydrolysis and absorption of the suture is complete between 91 and 18

119 days post-implantation72. Poliglecaprone 25 is marketed under the names

Monocryl72 (Ethicon), Petcryl Mono73 (Dolphin), DemeCAPRONE74 (DemeTech),

Monoglyde75 (Sutures India). Monocryl Plus76 (Ethicon) is another available poliglecaprone 25 suture that is coated with Irgacare MP to provide an antibiotic barrier during wound healing. Sterilization of poliglecaprone 25 is achieved through the use of ethylene oxide gas77.

Poly(lactide-co-ε-caprolactone):

Poly(lactide-co-ε-caprolactone), also known as P(LA/CL), was first reported in 1998 as a potential suture material. Taking commonly used monomers for suture, the authors were able to demonstrate a copolymer comprised of 75% lactide and 25% ε- caprolactone could be synthesized through ring opening polymerization. Currently, the only commercially available P(LA/CL) suture is Surgisorb M (Sutures - UK) and it is available either undyed or dyed with D&C Violet #2. It is a monofilament suture in sizes

8-0 through 2 and is coated with a mixture of calcium stearate and

P(LA/CL)78. Research suggests that P(LA/CL) sutures maintain 75% of their initial tensile strength after a period of 4 weeks, and lose all tensile strength after 25 weeks. The author was unable to find a 510(K) approval for this suture by the FDA, but the polymer has received clearance as part of a nerve capping device79 and as an absorbable sheet for wound support80.

Copolymers of three monomers: Poly(glycolide-co-trimethylene carbonate-co-ε-caprolactone):

Poly(glycolide-co-trimethylene carbonate-co-ε-caprolactone), commonly known as

Monosyn, is a suture manufactured by Aesculap. Monosyn is a triblock copolymer composed of 72% glycolide, 14% trimethylene carbonate, and 14% ε-caprolactone. As a triblock polymer, Monosyn has an ABA structure. In this naming scheme, the A block is polyglycolide, the rigid component of the polymer. The B block, that imparts flexibility, is the block copolymer poly(glycolide-co-trimethylene carbonate-co-ε-caprolactone). In order to synthesize the final polymer the soft segment is first polymerized in the melt at a temperature above 150°C to produce the dihydroxy terminated terpolymer. The terpolymer is then melted along glycolide between 200 and 250°C. This is performed in the presence of an appropriate catalyst or bifunctional initiator. Through this reaction, synthesis of the final ABA triblock copolymer is realized81. The polymer is then melt spun into a water bath before being stretched and annealed. Monosyn is an uncoated monofilament suture and is available undyed or dyed with D&C Violet #2. It maintains

50% of its tensile strength at two weeks post implantation. Hydrolysis is complete within

60-90 days post implantation. Monosyn is available in USP sizes 7-0 through

2. Sterilization of Monosyn is achieved through the use of ethylene oxide gas82.

Poly(glycolide-co-trimethylene carbonate-co-p-dioxanone):

Poly(glycolide-co-trimethylene carbonate-co-p-dioxanone), also known as Glycomer

631, commonly known as Biosyn, is a suture manufactured by Covidien. Biosyn is a 20 triblock copolymer composed of 60% glycolide, 14% p-dioxanone, and 26% trimethylene carbonate. Like Monosyn, Biosyn is an ABA copolymer. However, unlike

Monosyn, the center block is not a terpolymer, rather it is a copolymer of 35% p- dioxanone and 65% trimethylene carbonate. This copolymer is capped with a copolymer containing at least 50% glycolide and less than 50% p-dioxanone. The ratio of the capping copolymer is adjusted to arrive at the final ratio for Glycomer

631. Biosyn is an uncoated monofilament suture that is available undyed or dyed with

D&C Violet #2. Hydrolysis is complete within 90-110 days post implantation. The degradation of Biosyn is comparable to Vicryl, with tensile strength maintained for three weeks, and approximately 8% remaining after four weeks. Detailed information on the degradation profile of Biosyn is not readily available. Biosyn is available in USP sizes 6-

0 to 1. Sterilization of Biosyn is achieved through the use of ethylene oxide gas83.

Poly(ε-caprolactone-co-trimethylene carbonate-co-p-dioxanone):

Poly(ε-caprolactone-co-trimethylene carbonate-co-p-dioxanone) is a material that is not currently marketed as a saleable suture, but that has shown promise as a potential suture material. A series of poly(trimethylene carbonate-co-ε-caprolactone)-block- poly(p-dioxanone) copolymers were synthesized through a two-step polymerization process. The synthetic polymers were evaluated for their potential as suture material. Hong et. al. concluded that the polymer consisting of 90% p-dioxanone, 5% trimethylene carbonate, and 5% ε-caprolactone had excellent potential as a suture material84. The suture began degrading between 120 and 150 days post implantation, and was completely absorbed between 210 and 240 days post implantation. This potential material was evaluated as an uncoated monofilament suture in vivo. The

21 performance of this material suggest that it is comparable to other monofilament sutures like PDSII and Maxon. 22

Copolymers of four monomers: Poly(glycolide-co-L-lactide-co-trimethylene carbonate-co-ε-caprolactone):

Poly(glycolide-co-L-lactide-co-trimethylene carbonate-co-ε-caprolactone), also known as polyglytone 6211, commonly known as Caprosyn, is unique in the world of synthetic suture. This is the only suture currently on the market that contains four different monomers. Caprosyn, manufactured by Covidien, is a suture for the short term approximation of tissue. Due to its quick degradation, Caprosyn offers an alternative to traditional gut suture that can invoke an inflammatory response in tissue85, 86. It maintains 60% of its initial tensile strength at 5 days post implantation and 20-30% at 10 days post implantation. Hydrolysis is essentially complete within 56 days post implantation. Caprosyn is an uncoated monofilament suture that is available undyed or dyed with D&C Violet #2. Caprosyn is available in USP sizes 6-0 to 1. Sterilization of

Caprosyn is achieved through the use of ethylene oxide gas87. 23

Nonabsorbable Suture: Polyamides:

There are two polyamides that have found use as nonabsorbable surgical suture, Nylon

6 and Nylon 6,6. Nylon 6, or polycaprolactam, is manufactured through the ring opening polymerization of ε-caprolactam. Nylon 6,6, is a copolymer manufactured through the polycondensation of hexamethylenediamine and adipic acid. Nylon sutures are available in both monofilament and braided configurations, depending on their intended application.

Braided suture is manufactured from Nylon 6,6 and is available either undyed or dyed black with logwood dye for enhanced visibility. Braided nylon 6,6 suture is available in sizes 6/0 through 1 and is marketed under the names Nurolon88 (Ethicon), wax coated89, and Surgilon90 (Covidien), silicone coated. Sterilization of monofilament nylon suture can be achieved either through gamma sterilization using Cobalt-6091 or ethylene oxide gas90.

Monofilament nylon suture is manufactured from both nylon 6 and nylon 6,6, and is available undyed, dyed black with logwood dye, dyed green with D&C Green #592, or dyed blue with D&C Blue #293. Monofilament nylon suture is available in sizes 11/0 through 2 and is marketed under the names Ethilon94 (Ethicon), Monosof95 (Covidien),

Dermalon95 (Covidien), and Nylon96 (Teleflex). Sterilization of monofilament nylon suture can be achieved either through gamma sterilization using Cobalt-6097 or ethylene oxide gas98. 24

Polyesters:

Polyethylene terephthalate, commonly referred to as PET or polyester, is a material used as a non-absorbable suture. Polyester sutures are available as monofilament sutures, or as braided suture with or without a coating of PTFE. It is available undyed, dyed green with D&C Green #6, or with green and undyed suture braided together. Braided suture offers the largest sizes with an available range of USP sizes

6/0 through 5. Monofilament sutures are available in USP sizes 11/0 through

8/0. Polyester suture is marketed under the names Mersilene99 (Ethicon), Procare100

(Dolphin Sutures), Cottony II101 (Deknatel - no coating), Polydek102 (Deknatel - light

PTFE coating), and Tevdek103 (Deknatel - heavy PTFE coating). Sterilization of polyester suture can be achieved either through gamma sterilization using Cobalt-60104 or ethylene oxide gas102.

The use of high molecular weight PET is also important to note for its applicability in cardiovascular applications. Several polyester sutures are available specifically for this purpose, and differ slightly from typical PET sutures. Suture made from high molecular weight PET are available with a variety of coatings and are either undyed or dyed green with D&C Green #6. These sutures are available in USP sizes 5 through

7/0. Ethibond Excel (Ethicon) is coated with polybutilate. Surgidac105 (Covidien) is available uncoated or coated with polybutylene adipate. Ti-Cron106 (Covidien) is coated with silicone. Sterilization of high molecular weight PET suture can be achieved either through gamma sterilization using Cobalt-60107 or ethylene oxide gas108. 25

Polybutylene terephthalate (PBT) is offered as a monofilament suture by B. Braun under the name Miralene. Limited information is available regarding this suture and it is not currently listed on the Aesculap sutures portfolio overview109.

Polybutesters (PBEs) are also utilized for the sutures Novafil110 (Covidien) and

Vascufil111 (Covidien). These sutures are composed of a copolymer of 84% butylene terephthalate and 16% poly(tetramethylene ether glycol). Covidien claims that this makes the sutures “creep resistant110” and that they are able to return to their original shape after edema recedes. As this suture offers more elasticity than traditional nonabsorbable sutures, it is able to stretch and retract with the swelling of the wound site, reducing the tissue damage incurred by the pulling of the suture112. This material is also more fray resistant than polypropylene and leads to fewer premature breakages111. Both sutures are monofilament sutures, but Vascufil is coated with

Polytribolate, an absorbable polymer composed of 51% ε-caprolactone, 9% glycolide, and 40% poloxamer 188113. Poloxamer 188 is a copolymer of polyoxyethylene and polyoxypropylene114. Novafil is available in USP sizes 2 through 7/0 and is offered either clear of dyed blue with copper phthalocyanine. Vascufil is available in sizes 2/0 through 7/0 and is dyed blue with copper phthalocyanine. Sterilization of polybutester sutures is achieved through gamma sterilization using Cobalt-60115, 116.

Poly(vinylidene fluorides):

Poly(vinylidene fluoride), or PVDF, is a non-absorbable suture that was developed to have similar handling characteristics to polyester and polypropylene suture, but that has less of a potential for clot formation than polyester suture and is less prone to failure than polypropylene. PVDF has been shown to be equivalent to polypropylene suture for 26 most applications, with improved handling and extended durability117. PVDF is an uncoated monofilament suture that is available in black or dyed blue with copper phthalocyanine. This suture is available in USP sizes 10/0 through 2 and is marketed under the names Resopren118 (Resorba), Centidene119 (Centenial), PVDF120

(Eye4Vision), PVDF121 (Daps Tech), and PVDF122 (Acufirm). Teflene is a name for

PVDF suture, that was trademarked by Peters Laboratories, but has since been abandoned123. Sterilization of PVDF sutures is achieved through the use of ethylene oxide gas124, although it is capable of undergoing gamma sterilization using Cobalt-

60124.

Poly(hexafluoropropylene-vinylidene fluoride) is a copolymer consisting of hexafluoropropylene and vinylidene fluoride and is marketed under the name

Pronova125 (Ethicon). The composition of monomers is dependent on the size of the suture and can range from 20% to 50% vinylidene fluoride. By incorporating an additional monomer into the structure, Ethicon claims to have improved the handling characteristics of PVDF by reducing the compliance without making the material

“stretchy126.” Pronova is an uncoated monofilament suture that is available either undyed or dyed blue with copper phthalocyanine. This suture is available in USP sizes

8/0 through 2/0. Sterilization of PVDF sutures is achieved through the use of ethylene oxide gas127.

Poly(tetrafluoroethylene):

Poly(tetrafluoroethylene), or PTFE, commonly known as Teflon, is a material that has found applications as both a suture and a suture coating. PTFE is an uncoated monofilament suture that is available in white, often paired with a black needle for 27 improved visibility. This suture is available in USP sizes 6/0 through 2/0 and is marketed under the names Cytoplast128 (Osteogenics), PTFE129 (Omnia), PTFE130

(Coreflon), Cyto Surg131 (Salvin), and Gore-Tex132 (Gore Medical). Gore-Tex suture does not adhere to USP sizes and is sold in cardiovascular (CV) sizes CV8 through

CV0133. These sizes roughly correspond to USP sizes 7/0 through 1. However, these sizes are based on the measurement of the suture prior to expansion. This is due to the fact that the suture is approximately 50% air by volume133. Gore-Tex is highly porous and expands to a diameter significantly larger than any other comparable suture. This results in the suture diameter being comparable to the needle diameter, reducing the void left when a needle penetrates through tissue134. This reduces the amount of bleeding that can occur through the opening. Additionally, the highly porous nature greatly reduces the stiffness of the suture, rendering it 100 times less stiff than a comparably sized polypropylene suture135. Sterilization of PTFE sutures is achieved through the use of ethylene oxide gas136.

Polyolefins:

Isotactic polypropylene, commonly abbreviated as PP, is widely used as a nonabsorbable monofilament suture. For over 40 years, polypropylene sutures have been used for cardiovascular surgeries as well as tissue approximation in surface injuries. Due to its long history of use, it is often used as the suture of choice where a nonabsorbable material is required. The majority of nonabsorbable sutures are targeted as alternatives to polypropylene suture as this is the established system for a nonabsorbable monofilament suture. Isotactic polypropylene is polymerized from propylene through the use of a Ziegler-Natta catalyst. It is available undyed or dyed

28 blue with copper phthalocyanine. PP suture is available in USP sizes 10/0 through 2 and is marketed under the names Prolene (Ethicon), Duracare (Dolphin Sutures),

Surgipro II (Covidien), Deklene II (Deknatel), Surulene (Suru), Premilene (B. Braun). In recent years, the use of syndiotactic polypropylene in suture form has been reported. Sterilization of polypropylene sutures is achieved through the use ethylene oxide gas.

Ultra-high molecular weight polyethylene:

Ultra-high molecular weight polyethylene (UHMWPE) is a version of polyethylene with a molecular weight in the range of 2 to 6 megadaltons137. Due to the extremely high molecular weight, UHMWPE suture is stronger than other sutures of the same size, allowing a smaller sized suture to be used when a certain tensile strength is needed138. UHMWPE is an uncoated braided suture that is available in USP sizes 5/0 through 5 and is marketed under the names Force Fiber139 (Teleflex), FiberWire140

(Arthrex), TigerWire141 (Arthrex), Orthocord142 (Depuy), PowerFiber143 (CP Medical), and CP-Fiber143 (CP Medical). Most UHMWPE sutures are cobraided with another polymer to impart color and favorable handling properties. PowerFiber is offered in white or white with a green polyethylene tracer. CP-Fiber is offered in white or with a blue or black polyethylene tracker. Force Fiber is offered in white and blue without the inclusion of a cobraided polymer. Green Force Fiber is the result of a cobraid between

UHMWPE and polyester. A green/white version, as well as a white/green version, is achieved in the same manner. A white/blue version is the result of a cobraid of

UHMWPE and blue polypropylene. A white/black version is the result of a cobraid of

UHMWPE and black nylon 6,6. Orthocord is a co-braid of 62% polydioxanone (Ethicon) 29 and 38% UHMWPE. The PDS can be dyed with either D&C Violet #2 or D&C Blue #6 to give the suture a blue or purple color. The PDS is also coated with a copolymer consisting of 90% ε-caprolactone and 10% glycolide144, 145. Sterilization of UHWMPE sutures is achieved through the use ethylene oxide gas139. 30

Future Direction: Barbed suture:

Several advancements have been made in the field of barbed, or knotless, suture. The addition of structures on the suture surface, situated opposite to the direction which the suture is drawn through the tissue, allows for the application of even force throughout the length of the suture. This also eliminates the need to tie knots in the suture along the length of the wound closure. Incorporation of this structure is achieved through the use of a cutting die146. A large suture is passed through a cutting die, with excess suture material being cut off to arrive at the final configuration. This offers the surgeon the ability to perform complex procedures, most frequently laparoscopic surgery, with less time and less blood loss147. Knotless sutures are offered in a variety of polymers including poly(p-dioxanone), poliglecaprone 25, polypropylene, and nylon. These are offered in USP sizes 5-0 through 1, and are marketed under the names Stratafix 148

(Ethicon), Quill 149 (Surgical Specialties Corporation), and V-Loc 150 (Covidien).

Poly(propylene oxide) suture:

A recent patent application has reported the use of poly(propylene oxide) (PPO) in the design of a block copolymer151. This suture is currently in development and is referred to as Voyager152. This marks the first synthetic absorbable suture that deviates from the five monomers approved for use by the FDA. The key benefit put forth by this device is a prolonged knot pull strength that surpasses even PDS suture. After approximately five weeks, there is a sharp decrease in the tensile strength of PDS 31 suture. While the PPO based suture has a lower initial tensile strength, the designers claim that the strength at time periods past five weeks is greater than that of PDS. This is key for the approximation of tissue that is slow to fully heal. For instance, in a laparotomy, where the abdominal wall is opened. The healing of the abdominal wall takes approximately two months in a healthy patient, but the healing time can be longer in many patients. The Voyager device would allow for the extended approximation of the abdominal wall and ensures full wound closure. This has the benefit of reducing incisional hernias, which are a fairly common occurrence in laparotomies (~20%). By their own estimation, this device has the potential to save $22.7 billion in healthcare costs in the United States due to a 50% reduction in incisional hernias.

Diacetyl Chitin Coated Suture153:

Diacetyl chitin (DAC) coated silk sutures have recently been suggested as an alternative to current suture technologies due to the natural abundance of chitin and the lack of bioreaction to this material. DAC silk sutures show similar degradation to current offerings and have comparable mechanical properties. Evaluation of the antibacterial activity and tensile strength show favorable comparison to commercial alternatives.

Additionally, the authors report that the natural antimicrobial properties of chitin has utility as a suture coating, and that the suture appears to accelerate the healing process compared to a control suture. Furthermore, chitin based dressings have been previously approved and are currently available on the market.

Antibiotic Eluting Suture154:

The introduction of an antibiotic into the body of a suture is something that currently has not been introduced into the market. Typical antibiotic loading for a suture material is

32 achieved during the coating phase, in which a suture is passed through a slurry containing the target compound. However, recently, an article has suggested the production of a suture using wet electrospinning of poly(L-lactide), PEG, and levofloxacin onto silk. The coated strands, with a 45 μm diameter, have the potential for application in fine size or braided suture. The authors report the release of antibiotic over the course of one week. Furthermore, the authors report that the handling characteristics of the silk suture is comparable to unaltered silk suture, but has antibiotic activity against staph and e. coli. The significant impact of this work is the demonstration of antibiotic loaded silk suture, something that is not currently offered in the suture market. As silk is the preferred material for suture in large parts of the world, the addition of antibiotic activity to this offers a significant impact on the silk suture market.

Amino Acid Based Nanogel Conjugated Suture155:

In a similar scope to the publication mentioned above, researchers have reported the introduction of a biodegradable nanogel containing triclosan to silk suture. By preparing an l-lysine macrogel loaded with Triclosan, and enzymatically degrading the macrogel using trypsin, the authors report the ability to produce nanogels containing triclosan.

The silk sutures are degummed in ethanol and then submerged in the nanogel to allow adhesion to the exterior. The authors report handling characteristics comparable to unaltered silk suture. With the introduction of Triclosan, a standard antibiotic that has been approved as a suture coating material, this material offers a possible alternative to traditional silk suture. 33

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