CN110769866B - Surgical stapler with controlled healing - Google Patents

Abstract

The present invention provides methods and devices for promoting wound healing. In general, surgical stapler and staple assemblies are provided having an effective amount of at least a Matrix Metalloproteinase (MMP) inhibitor that is effective to prevent MMP-mediated extracellular matrix degeneration during wound healing in tissue.

Description

Surgical stapler with controlled healing

Technical Field

The present invention provides surgical stapling instruments and methods that allow for control of the healing cascade of stapled tissue.

Background

Surgical staplers are used in surgical procedures to close openings in tissues, vessels, ducts, shunts, or other objects or body parts involved in a particular procedure. These openings may be naturally occurring, such as blood vessels or passages in internal organs like the stomach, or they may be formed by the surgeon during surgery, such as by puncturing tissue or blood vessels to form bypasses or anastomoses or by cutting tissue during a stapling procedure.

Most staplers have a handle with an elongated shaft having a pair of movable opposed jaws formed on the ends thereof for holding and forming staples between the jaws. The staples are typically housed in a staple cartridge that can house a plurality of rows of staples and are typically disposed in one of two jaws for ejection of the staples to a surgical site. During use, the jaws are positioned such that an object to be stapled is disposed between the jaws, and the staples are ejected and formed when the jaws are closed and the device is actuated. Some staplers include a knife configured to travel between rows of staples in the staple cartridge to longitudinally cut and/or open stapled tissue between the rows of staples.

Although surgical staplers have improved over the years, they still present themselves with a number of problems. One common problem is that when the staples penetrate tissue or other objects in which the staples are disposed, leakage can occur from the staple forming holes. Blood, air, gastrointestinal fluids, and other fluids may seep through the openings formed by the staples, even after the staples are fully formed.

Accordingly, there remains a need for improved devices and methods for suturing tissue, vessels, catheters, shunts, or other objects or body parts that minimize leakage at the staple insertion site.

Disclosure of Invention

In general, surgical staplers and components thereof are provided that allow for control of the healing cascade of the stapled tissue. In particular, surgical staples and components thereof are provided having at least one releasable Matrix Metalloproteinase (MMP) inhibitor for delivery to tissue surrounding the staple site.

In one aspect, a staple cartridge assembly for use with a surgical stapler is provided and includes a cartridge body. The cartridge body has a plurality of staple cavities. Each staple cavity may have a surgical staple disposed therein. The cartridge body can also optionally have a biocompatible adjunct material releasably retained thereon and configured to be delivered to tissue by deployment of the staples in the cartridge body. The cartridge assembly may further include an effective amount of at least one Matrix Metalloproteinase (MMP) inhibitor effective to control a healing cascade in the stapled tissue and to prevent MMP-mediated extracellular matrix degeneration during healing of the wound in the tissue in a predetermined manner.

In one embodiment, the at least one MMP inhibitor can be disposed on at least a portion of the plurality of staples, such as on at least one of the first leg, the second leg (including the distal tips of the first leg and the second leg), and the crown of the plurality of staples. In other aspects, an effective amount of at least one MMP inhibitor can be disposed within and releasable from the adjunct material. MMP inhibitors can be configured to inhibit one or more of the following: MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP23A, MMP23B, MMP25, MMP25, MMP26, MMP27, and MMP 28. The MMP inhibitor can be configured to inhibit collagenase, gelatinase, stromelysin, or membrane-type MMPs. The MMP inhibitor can be a tissue inhibitor of a metalloprotease (TIMP, such as any of TIMP1, TIMP2, TIMP3, or TIMP 4). The MMP inhibitor may be one or more of the following: hydroxy acid salts, carboxylic acid salts, carbamoylphosphonic acid salts, hydroxyurea, hydrazine, beta-lactams, squaric acid, nitrogen-containing ligands, thiols, and phosphonoidene groups. In some embodiments, the MMP inhibitor can prevent inflammatory cells from being attracted to tissue following staple deployment.

In another aspect, an end effector for a surgical instrument is provided that, in one implementation, has a first jaw having a cartridge body with a plurality of staple cavities configured to seat staples therein and a second jaw having an anvil having a plurality of staple-forming cavities formed on a tissue-facing surface thereof. At least one of the first jaw and the second jaw may be movable relative to the other. In some implementations, the end effector can further include a biocompatible adjunct material releasably retained on the cartridge body that is configured to be delivered to tissue by deployment of the staples in the cartridge body. The end effector can include an effective amount of at least one Matrix Metalloproteinase (MMP) inhibitor effective to prevent MMP-mediated extracellular matrix degeneration during healing of the wound in a predetermined manner in tissue.

In another aspect, a method for temporarily inhibiting wound healing at a surgical site following surgical stapling of tissue with a surgical stapler is provided. In one embodiment, the method can include engaging tissue between a cartridge assembly of an end effector and an anvil, and actuating the end effector to eject staples from the cartridge assembly into the tissue. The method may optionally include attaching an adjunct material to an end effector of a surgical stapler, and extending staples through the adjunct material to retain the adjunct material at the surgical site. At least one of a portion of the plurality of staples and an optional adjunct material attachable to an end effector of a surgical stapler can include an effective amount of at least one Matrix Metalloproteinase (MMP) inhibitor. Release of MMP inhibitors into the tissue surrounding the staple insertion site can prevent MMP-mediated extracellular matrix degeneration during wound healing in the tissue in a predetermined manner.

In one embodiment, the at least one MMP inhibitor can be disposed on at least a portion of the plurality of staples, such as on at least one of the first leg, the second leg (including the distal tips of the first leg and the second leg), and the crown of the plurality of staples. An effective amount of at least one MMP inhibitor can be disposed within and releasable from the adjunct material. MMP inhibitors can be configured to inhibit one or more of the following: MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP23A, MMP23B, MMP25, MMP25, MMP26, MMP27, and MMP 28. The MMP inhibitor can be configured to inhibit collagenase, gelatinase, stromelysin, or membrane-type MMPs. The MMP inhibitor can be a tissue inhibitor of a metalloprotease (TIMP, such as any of TIMP1, TIMP2, TIMP3, or TIMP 4). The MMP inhibitor may be one or more of the following: hydroxy acid salts, carboxylic acid salts, carbamoylphosphonic acid salts, hydroxyurea, hydrazine, beta-lactams, squaric acid, nitrogen-containing ligands, thiols, and phosphonoidene groups. In some embodiments, the MMP inhibitor can prevent inflammatory cells (e.g., at least one of neutrophils, helper T cells, and macrophages) from being attracted to tissue following staple deployment. In some aspects, the tissue may be colon tissue, such as colon tissue following surgical resection.

Drawings

The present invention will be more fully understood from the detailed description given below in conjunction with the accompanying drawings, in which:

FIG. 1 is a perspective view of one embodiment of a surgical stapler.

FIG. 2 is an exploded view of the distal portion of the surgical stapler of FIG. 1.

FIG. 3 is a perspective view of a firing bar of the surgical stapler of FIG. 1, the firing bar having an E-beam at a distal end thereof.

FIG. 4 is a perspective view of another embodiment of a surgical stapler.

FIG. 5 is a perspective view of another embodiment of a surgical stapler.

Detailed Description

Certain exemplary embodiments will now be described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the devices and methods disclosed herein. One or more examples of these embodiments are illustrated in the accompanying drawings. Those skilled in the art will understand that the devices and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope of the present disclosure is defined solely by the claims. Features illustrated or described in connection with one exemplary embodiment may be combined with features of other embodiments. Such modifications and variations are intended to be included within the scope of the present invention.

Moreover, in the present disclosure, similarly named components in various embodiments typically have similar features, and thus, in a particular embodiment, each feature of each similarly named component is not necessarily fully set forth. Further, to the extent that linear or circular dimensions are used in the description of the disclosed systems, devices, and methods, such dimensions are not intended to limit the types of shapes that may be used in connection with such systems, devices, and methods. Those skilled in the art will recognize that the equivalent dimensions of such linear and circular dimensions can be readily determined for any geometric shape. The size and shape of the systems and devices and their components may depend at least on the anatomy of the subject in which the systems and devices are to be used, the size and shape of the components with which the systems and devices are to be used, and the methods and procedures in which the systems and devices are to be used.

It should be understood that the terms "proximal" and "distal" are used herein with respect to a user, such as a clinician, grasping a handle of an instrument. Other spatial terms such as "anterior" and "posterior" similarly correspond to distal and proximal, respectively. It will also be appreciated that, for convenience and clarity, spatial terms such as "vertical" and "horizontal" are used herein in connection with the drawings. However, surgical instruments are used in many orientations and positions, and these spatial terms are not intended to be limiting and absolute.

Various exemplary devices and methods for performing a surgical procedure are provided. In some embodiments, devices and methods are provided for open surgery, and in other embodiments, devices and methods for laparoscopic, endoscopic, and other minimally invasive surgical procedures. These devices may be fired directly by a human user or remotely under the direct control of a robot or similar manipulation tool. However, those skilled in the art will appreciate that the various methods and devices disclosed herein may be used in many surgical procedures and applications. Those skilled in the art will further appreciate that the various instruments disclosed herein may be inserted into the body in any manner, such as through a natural orifice, through an incision or puncture made in tissue, or through an access device (such as a trocar cannula). For example, the working portion or end effector portion of the instrument can be inserted directly into the body of a patient or can be inserted through an access device having a working channel through which the end effector and elongate shaft of the surgical instrument can be advanced.

During the surgical procedure, the patient's tissue may be traumatized (e.g., cut, torn, punctured, etc.) in any of a variety of ways. A wound may be a desired aspect of a surgical procedure, such as in an anastomosis procedure and/or when cutting and fastening tissue using a surgical device, such as a surgical stapler. The injured tissue typically heals in approximately the same way over a period of time for all patients.

Wound healing is traditionally thought to involve four phases: hemostasis, inflammation, proliferation and remodeling. The hemostasis stage typically involves coagulation, e.g., to stop bleeding. Generally, damaged blood vessels contract to slow blood flow, platelets aggregate to help seal the wound site, platelets activate fibrin to further promote wound sealing, and blood clots form at the wound site. The inflammatory phase typically involves the debridement of the wound site. Generally, the immune system responds to the threat of possible infection at the wound site by signaling defensive immune cells such as neutrophils and macrophages. The proliferative phase typically involves the reconstruction of tissue by tissue growth and angiogenesis (blood vessel growth). Generally, fibroblasts reach the wound site, deposit collagen, release growth factors that attract epithelial cells, and epithelial cells attract endothelial cells. The remodeling stage, also known as the maturation stage, generally involves strengthening scar tissue at the wound site. Typically, collagen fibers align and cross-link, and the scar matures and eventually disappears.

Although each of the four phases of wound healing involves different aspects of the healing process, these phases typically overlap one another. That is, each of the last three phases typically overlaps with its previous phase, e.g., the inflammatory phase overlaps with the hemostatic phase, the proliferative phase overlaps with the inflammatory phase, and the remodeling phase overlaps with the proliferative phase. The rate at which the transition between stages occurs typically affects the rate of overall wound healing and, therefore, typically affects the recovery time of the patient, the chance of complications arising and/or the comfort of the patient. Similarly, the length of each of the four independent phases generally affects the speed of overall wound healing and overall recovery of the patient.

Matrix Metalloproteinases (MMPs) are a family of proteases that break down the extracellular matrix (ECM) components of tissues under a variety of physiological and pathological conditions, including during wound healing. These enzymes remove dead and devitalized tissue, help remodel underlying connective tissue of the ECM, promote migration of inflammatory cells into the wound site, and aid in angiogenesis.

During the inflammatory phase of wound healing, MMPs break down damaged ECM located at the wound margin. This enables new ECM molecules (such as, for example, collagen, elastin, and fibronectin) synthesized by cells located at or attracted to the wound site during later stages of wound healing to eventually coalesce into and become part of the intact ECM, thereby causing the wound to close and heal. In addition, expression of certain MMPs (e.g., MMP1, MMP9, and MMP8) that follow the wound are associated with recruitment of pro-inflammatory immune cells to the site of wound formation (such as, but not limited to, neutrophils, helper T cells, and macrophages) and expression of pro-inflammatory substances and proteins.

As discussed in more detail in the examples section, following tissue suturing, cells present at the staple insertion site release MMPs that initiate processes that degrade the ECM (specifically, the collagen component of the ECM) at and near the wound caused by staple insertion to facilitate the initial stages of wound healing. However, without being bound by theory, and as shown in the examples, it is believed that this natural process may at least initially (i.e., up to about three days after staple insertion) cause tissue weakening around the staple site (e.g., due to denaturation of collagen in the ECM), thereby rendering it susceptible to tearing and other complications (such as leakage of blood, air, and other fluids through the openings formed by the staples, and, for example, anastomotic leakage following bowel resection). Thus, and again without being bound by theory, it is believed that delivering a substance capable of inhibiting MMPs to a wound site in tissue (e.g., intestinal tissue) following staple insertion can prevent or minimize ECM degeneration associated with the initial phase of wound healing, thereby strengthening the staple insertion site and making it less likely to leak or rupture.

Accordingly, it may be desirable to use one or more MMP inhibitors in conjunction with a surgical instrument (such as a surgical stapler) to help improve surgery. MMP inhibitors are molecules capable of inhibiting or reducing the proteolytic activity of MMPs on ECM components at a wound site. In addition, MMP inhibition formed immediately following the wound can prevent additional pro-inflammatory immune cells from being attracted to the wound site, which can lead to further structural weakening of the ECM. Without being bound by theory, by preventing native MMP-mediated degradation of the ECM that occurs immediately following staple insertion, MMP inhibitors may be able to prevent tissue leakage complications associated with tissue stapling by strengthening the tissue surrounding the wound site. In some cases, MMP inhibitors provided by the devices and delivered to the tissue stapling site according to methods provided herein can increase the incidence of scar tissue formation, resulting in minimized tissue movement within and around the staple puncture site, which can occur from tissue deformation (e.g., lung inflation, gastrointestinal tract distension, etc.) that occurs after stapling. Those skilled in the art will recognize that the staple puncture site may act as a stress concentrator and that the size of the hole formed by the staple will increase when the tissue surrounding it is under tension. Thus, limiting tissue movement around these puncture sites by preventing MMP-mediated ECM degradation (e.g., MMP-mediated proteolysis of collagen) can promote scar tissue formation and thereby minimize pore size that can grow under tension and the potential for leakage.

Additional clinical studies involving MMPs and the use of MMP inhibitors in wound healing can be found in the following documents: argen et al, Surgery,2006,140(1): 72-82; krareup et al, Int J color Dis,2013, 28: 1151-1159; bosmans et al, BMC Gastroenterology (2015) 15: 180 of the total weight of the composition; holte et al, brit.j.surg.,2009, 96: 650-54; siemonsma et al, Surgery,2002,133(3): 268-276; klein et al, eur.surg.res.,2011, 46: 26-31; moran et al, World j. expression Surgery,2007, 2: 13; kaemmer et al, j.surg.res.,2010, I63, e67-e 72; martens et al, Gut,1991,32, 1482-87; fatouros et al, 1999, Eur.J.Surg.,165(10) 986-92; savage et al, 1997,40(8): 962-70; oines et al, World J Gastroenterol, 201420 (35) 12637-48; kiyama et al, Wound Repair and Regen, 10(5): 308-13; raptis et al, int.j.colorectal dis, 2011; de hindh et al, int.j.colorect.dis., 2002, 17: 348-54; and Hayden et al, 2011, j.surgical res, 168: 315-324, the disclosure of each of which is incorporated herein by reference in its entirety.

Surgical stapling instrument

A variety of surgical instruments can be used in conjunction with one or more of the agents disclosed herein. The surgical instrument may comprise a surgical stapler. A variety of surgical staplers can be used, such as linear surgical staplers and circular staplers. In general, a linear stapler can be configured to produce a longitudinal staple line and can include an elongated jaw having a cartridge coupled thereto that contains a longitudinal row of staples. The elongate jaws can include a knife or other cutting element configured to create a cut between the staple rows along the tissue held within the jaws. In general, circular staplers can be configured to form a circular staple line and can include circular jaws with a cartridge that houses a circular row of staples. The circular jaws can include a knife or other cutting element configured to form a cut within the staple row to define an opening through tissue held within the jaws. In a variety of different surgical procedures, the stapler can be used for a variety of different surgical procedures on a variety of tissues, such as chest surgery or gastric surgery.

FIG. 1 illustrates one example of a linearsurgical stapler 10 suitable for use with one or more appendages and/or one or more medicants. Thestapler 10 generally includes a handle assembly 12, ashaft 14 extending distally from a distal end 12d of the handle assembly 12, and anend effector 30 located at a distal end 14d of theshaft 14. Theend effector 30 has opposed lower and upper jaws 32, 34, although other types of end effectors may be used with theshaft 14, handle assembly 12, and components associated therewith. Lower jaw 32 has astaple channel 56 configured to supportstaple cartridge 40, and upper jaw 34 has an anvil surface 33 facing lower jaw 32 and configured to operate as an anvil to assist in deploying staples in staple cartridge 40 (the staples are obscured in fig. 1 and 2). At least one of the opposing lower and upper jaws 32, 34 is movable relative to the other of the lower and upper jaws 32, 34 to clamp tissue and/or other objects disposed therebetween. In some implementations, one of the opposing lower and upper jaws 32, 34 can be fixed or otherwise immovable. In some implementations, both of the opposing lower and upper jaws 32, 34 can be movable. Components of the firing system can be configured to pass through at least a portion of theend effector 30 to eject staples into clamped tissue. In various implementations, a blade 36 or other cutting element may be associated with the firing system to cut tissue during the stapling procedure.

Operation of theend effector 30 may begin with input at the handle assembly 12 by a user (e.g., clinician, surgeon, etc.). The handle assembly 12 can have many different configurations designed to manipulate and operate theend effector 30 associated therewith. In the illustrated example, the handle assembly 12 has a pistol-grip type housing 18 having a variety of mechanical and/or electronic components disposed therein to operate various features of theinstrument 10. For example, the handle assembly 12 can include a knob 26 mounted adjacent its distal end 12d that can facilitate rotation of theshaft 14 and/or theend effector 30 relative to the handle assembly 12 about the longitudinal axis L of theshaft 14. The handle assembly 12 can further include a clamping component as part of a clamping system actuated by the clampingtrigger 22 and a firing component as part of a firing system actuated by the firingtrigger 24. The clampingtrigger 22 and the firingtrigger 24 may be biased to an open position relative to thestationary handle 20, such as by torsion springs. Movement of the clampingtrigger 22 toward the fixation handle 20 can actuate the clamping system, which, as described below, can collapse the jaws 32, 34 toward one another and thereby clamp tissue therebetween. Movement of the firingtrigger 24 may actuate a firing system, which, as described below, may eject staples from astaple cartridge 40 disposed therein and/or advance a blade 36 to sever tissue captured between the jaws 32, 34. Those skilled in the art will recognize that components of various configurations for the firing system (mechanical, hydraulic, pneumatic, electromechanical, robotic, or other) may be used to fire staples and/or cut tissue.

As shown in fig. 2, the embodiedend effector 30 is shown having a lower jaw 32 that acts as a cartridge assembly or carrier and an opposing upper jaw 34 that acts as an anvil. Astaple cartridge 40 having a plurality of staples therein is supported in a staple tray 37, which in turn is supported within the cartridge channel of the lower jaw 32. The upper jaw 34 has a plurality of staple forming pockets (not shown), each of which is positioned above a corresponding staple from the plurality of staples contained within thestaple cartridge 40. Although in the particular implementation shown, the upper jaw 34 has aproximal pivot end 34p only distally of its engagement with theshaft 14 that is pivotally received within the proximal end 56p of thestaple channel 56, the upper jaw 34 can be connected to the lower jaw 32 in a variety of ways. As the upper jaw 34 pivots downwardly, the upper jaw 34 moves the anvil surface 33 and the staple forming pockets formed thereon toward the opposingstaple cartridge 40.

Opening and closing of the jaws 32,34 to selectively clamp tissue therebetween can be accomplished using a variety of clamping components. As shown, the pivotingend 34p of the upper jaw 34 includes a closure feature 34c distal to its pivotal attachment to thestaple channel 56. Thus, in response to the clampingtrigger 22, theclosure tube 46 selectively imparts an opening motion to the upper jaw 34 during proximal longitudinal movement of theclosure tube 46 and a closing motion to the upper jaw 34 during distal longitudinal movement of the closure tube, the distal end of which includes a horseshoe aperture 46a that engages the closure feature 34 c. As noted above, in various implementations, opening and closing of theend effector 30 can be accomplished by relative motion of the lower jaw 32 with respect to the upper jaw 34, relative motion of the upper jaw 34 with respect to the lower jaw 32, or motion of both jaws 32,34 with respect to each other.

The firing component of the illustrated embodiment includes a firing bar 35 having an E-beam 38 on its distal end as shown in FIG. 3. The firing bar 35 is included within theshaft 14, e.g., in a longitudinal firing bar slot 14s of theshaft 14, and is guided by the firing motion from the handle 12. Actuation of the firingtrigger 24 may affect distal motion of the E-beam 38 through at least a portion of theend effector 30 to thereby cause firing of staples contained within thestaple cartridge 40. As shown, a guide 39 projecting from a distal end of the E-beam 38 can engage a wedge sled 47, shown in FIG. 2, which in turn can push staple drivers 48 upwardly through staple cavities 41 formed in thestaple cartridge 40. The upward movement of the staple drivers 48 applies an upward force to each of the plurality of staples within thecartridge 40, thereby pushing the staples upward against the anvil surface 33 of the upper jaw 34 and producing formed staples.

In addition to enabling staple firing, the E-beam 38 can be configured to facilitate closure of the jaws 32, 34, spacing of the upper jaw 34 relative to thestaple cartridge 40, and/or severing of tissue captured between the jaws 32, 34. Specifically, a pair of top pins and a pair of bottom pins can engage one or both of the upper and lower jaws 32, 34 to compress the jaws 32, 34 toward one another as the firing bar 35 is advanced through theend effector 30. At the same time, a knife 36 extending between the top and bottom pins may be configured to sever tissue captured between the jaws 32, 34.

In use,surgical stapler 10 may be disposed in a cannula or port and at a surgical site. Tissue to be cut and stapled may be placed between the jaws 32, 34 of thesurgical stapler 10. Features of thestapler 10 can be manipulated by a user as needed to achieve a desired position of the jaws 32, 34 at the surgical site and tissue relative to the jaws 32, 34. After proper positioning has been achieved, the clampingtrigger 22 may be pulled toward thestationary handle 20 to actuate the clamping system. Thetrigger 22 may operate components of the clamping system such that theclosure tube 46 is advanced distally through at least a portion of theshaft 14 to cause at least one of the jaws 32, 34 to collapse toward the other to clamp tissue disposed therebetween. Thetrigger 24 can then be pulled toward thestationary handle 20 to operate the components of the firing system such that the firing bar 35 and/or the E-beam 38 are advanced distally through at least a portion of theend effector 30 to effect the firing of the staples and optionally sever tissue captured between the jaws 32, 34.

Another example of a surgical instrument in the form of a linear surgical stapler 50 is shown in fig. 4. Stapler 50 may be generally constructed and used similarly to stapler 10 of FIG. 1. Similar to thesurgical instrument 10 of fig. 1, the surgical instrument 50 includes a handle assembly 52 having a shaft 54 extending distally therefrom and having an end effector 60 on a distal end thereof for treating tissue. The upper and lower jaws 64, 62 of the end effector 60 can be configured to capture tissue therebetween, staple the tissue by firing staples from a cartridge 66 disposed in the lower jaw 62, and/or create an incision in the tissue. In this implementation, the attachment portion 67 on the proximal end of the shaft 54 may be configured to allow the shaft 54 and the end effector 60 to be removably attached to the handle assembly 52. In particular, the mating feature 68 of the attachment portion 67 may mate with a complementary mating feature 71 of the handle assembly 52. The mating features 68, 71 may be configured to be coupled together via, for example, a snap-fit coupling, a bayonet coupling, or the like, although any number of complementary mating features and any type of coupling may be used to removably couple the shaft 54 to the handle assembly 52. While the entire shaft 54 of the illustrated implementation is configured to be detachable from the handle assembly 52, in some implementations, the attachment portion 67 may be configured to allow only a distal portion of the shaft 54 to be detachable. The detachable coupling of shaft 54 and/or end effector 60 may allow for selective attachment of a desired end effector 60 for a particular procedure, and/or reuse of handle assembly 52 for a plurality of different procedures.

Handle assembly 52 may have one or more features thereon for manipulating and operating end effector 60. As a non-limiting example, a knob 72 mounted on a distal end of handle assembly 52 may facilitate rotation of shaft 54 and/or end effector 60 relative to handle assembly 52. The handle assembly 52 can include a clamping component as part of a clamping system that is actuated by the movable trigger 74 and a firing component as part of a firing system that can also be actuated by the trigger 74. Thus, in some implementations, movement of the trigger 74 toward the fixed handle 70 through the first range of motion can actuate the clamping component such that the opposing jaws 62, 64 are approximated to one another to achieve the closed position. In some implementations, only one of the opposingjaws 62, 24 can be moved to the closed position of the jaws 62, 64. Further movement of the trigger 74 toward the stationary handle portion 70 through a second range of motion can actuate the firing components such that staples are ejected from the staple cartridge 66 and/or advancement of a knife or other cutting element (not shown) severs tissue captured between the jaws 62, 64.

One example of a surgical instrument in the form of a circular surgical stapler 80 is shown in FIG. 5. Stapler 80 may be generally constructed and used similarly tolinear staplers 10, 50 of FIGS. 1 and 4, but with some features adapted for its function as a circular stapler. Similar to thesurgical instruments 10, 50, the surgical instrument 80 includes a handle assembly 82 and a shaft 84 extending distally therefrom and having an end effector 90 on a distal end thereof for treating tissue. The end effector 90 may include a cartridge assembly 92 and an anvil 94 each having a tissue contacting surface that is substantially circular in shape. The cartridge assembly 92 and anvil 94 can be coupled together via a shaft 98 extending from the anvil 94 to the handle assembly 82 of the stapler 80, and the actuator 85 on the manipulating handle assembly 82 can retract and advance the shaft 98 to move the anvil 94 relative to the cartridge assembly 92. The anvil 94 and cartridge assembly 92 can perform various functions, and can be configured to capture tissue therebetween, staple the tissue by firing staples from a cartridge 96 of the cartridge assembly 92, and/or can create an incision in the tissue. Generally, the cartridge assembly 92 can house a cartridge comprising staples and can deploy the staples against the anvil 94 to form a circular staple pattern, such as staples around the circumference of a tubular body organ.

In one implementation, the shaft 98 may be formed from first and second portions (not shown) that are configured to be releasably coupled together to allow the anvil 94 to be separated from the cartridge assembly 92, which may allow for greater flexibility in positioning the anvil 94 and cartridge assembly 92 in the body of a patient. For example, a first portion of the shaft can be disposed within the cartridge assembly 92 and extend distally beyond the cartridge assembly 92, terminating in a distal mating feature. A second portion of the shaft 84 can be disposed within the anvil 94 and extend proximally out of the cartridge assembly 92, terminating in a proximal mating feature. In use, the proximal and distal mating features may be coupled together to allow the anvil 94 and cartridge assembly 92 to move relative to one another.

Handle assembly 82 of stapler 80 can have various actuators disposed thereon that can control the movement of the stapler. For example, the handle assembly 82 may have a knob 86 disposed thereon to facilitate positioning of the end effector 90 via rotation, and/or a trigger 85 for actuation of the end effector 90. Movement of the trigger 85 toward the stationary handle 87 through the first range of motion can actuate components of the clamping system to approximate the jaws, i.e., move the anvil 94 toward the cartridge assembly 92. Movement of the trigger 85 toward the stationary handle 87 through the second range of motion can actuate components of the firing system to deploy staples from the staple cartridge assembly 92 and/or advance a knife to sever tissue captured between the cartridge assembly 92 and the anvil 94.

The illustrated examples ofsurgical stapling instruments 10, 50, and 80 provide but a few examples of the many different configurations and associated methods of use that can be used in conjunction with the disclosure provided herein. While the illustrated examples are each configured for minimally invasive surgery, it will be appreciated That instruments configured for open surgery, such as an open linear stapler as described in U.S. patent 8,317,070 entitled "Surgical Devices, product Formed Staples," filed on 28.2.2007, may be used in conjunction with the disclosure provided herein. More details regarding the illustrated examples, as well as additional examples of surgical staplers, components thereof, and associated methods of use, are provided in the following patents: U.S. patent publication 2013/0256377 entitled "Layer Comprising applicable documents" filed on 8.2.2013, U.S. patent 8,393,514 entitled "selecting orthogonal applicable Fastener cards" filed on 30.9.2010, U.S. patent 8,317,070 entitled "scientific supporting Devices third product Formed services trees" filed on 28.2007, U.S. patent 7,143,925 entitled "scientific supporting Devices third product Formed services patents" filed on 21.6.2005, U.S. patent publication 7,143,925 entitled "scientific instrumentation locking Devices", U.S. patent publication 2015/0134077 entitled "filed on 8.11.2013, U.S. patent publication 2015/0134076 entitled" adapting Materials In documents filed on 8.11.8.2013, U.S. patent publication 2015/0134076 entitled "optimizing Materials publication For Use supporting Devices" filed on 8.11.8.11, U.S. patent publication 2015/0134077 entitled "filing product compatible publication For obtaining applications In documents" filed on 8.3.8.8.S. patent publication 2013, U.S. patent publication 2015/0133996 entitled "position Charged Implantable Materials and Method of Forming the Same" filed on 8.11.2013, U.S. patent publication 2015/0129634 entitled "Tissue advancement Materials and Method of Using the Same" filed on 8.11.2013, U.S. patent publication 2015/0133995 entitled "Hybrid attachment Materials for Use in surgery" filed on 8.11.2014, U.S. patent application 14/226,142 entitled "Surgical Instrument for Use in surgery" filed on 26.3.2014, and U.S. patent application System 14/300,954 entitled "attachment Materials and Method for Use in surgery" filed on 10.6.2014 are hereby incorporated by reference in their entireties.

MMP inhibitors

MMPs of a family comprising more than 20 members use Zn in their active site²⁺ To catalyze hydrolysis of ECM components such as collagen. Based on their substrate specificity, they can be broadly classified into three subfamilies: collagenase, stromelysin and gelatinase. The MMP family of proteins is involved in the breakdown of extracellular matrix in normal physiological processes such as embryonic development, reproduction, angiogenesis, bone development, wound healing, cell migration, learning and memory, as well as in pathological processes such as arthritis, intracerebral hemorrhage and metastasis. Most MMPs are secreted as inactive proproteins, which are activated when cleaved by extracellular proteases. The enzyme encoded by this gene degrades type IV and type V collagen and other extracellular matrix proteins.

Under normal physiological conditions, MMPs play a role in wound healing and tissue remodeling. However, when these enzymes are over-activated, they can over-degrade the ECM, resulting in a disease condition. For example, MMP-2 and MMP-9 (both gelatinases) are thought to be involved in the pathogenesis of inflammatory, infectious, and neoplastic diseases in many organs. Excessive activation of MMP-8 (also known as collagenase-2 or neutrophil collagenase) is associated with diseases such as emphysema and osteoarthritis. See Balbin et al, "collagen 2(MMP-8) expression in muscle tissue-modification processes, analysis of matter potential role in postspecific accumulation of the said uterus", J.biol.chem.,273(37): 23959-. Excessive activation of MMP-12 (also known as macrophage elastase or metalloelastase) plays a key role in tumor invasion, arthritis, atherosclerosis, alport syndrome, and Chronic Obstructive Pulmonary Disease (COPD). MMP-1 and MMP-13 are involved in the proteolysis of collagen. Excessive degradation of collagen is associated with the development of a variety of diseases, including osteoarthritis. See, e.g., P.G.Mitchell et al, "Cloning, expression, and type II collagenic activity of matrix metalloproteinase-13from human osteoinductive cartilage", J.Clin invent.1996, 2.month 1; 97(3):761-768.

As used herein, a "matrix metalloproteinase inhibitor" or "MMP inhibitor" is any compound that inhibits at least five percent (such as inhibits any of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) of the proteolytic activity of at least one matrix metalloproteinase that is naturally occurring in a mammal (such as MMPs naturally expressed during wound healing). Many MMP inhibitors are known in the art. For example, existing MMP inhibitors can be based on hydroxamic acid derivatives, sulfonyl amino acids, and sulfonyl amino hydroxamic acid derivatives. The hydroxamic acid moiety in these inhibitors binds to the MMP active site Zn²⁺ To inhibit enzyme activity. In addition, many peptides are known inhibitors of matrix metalloproteinases.

Non-limiting specific examples of matrix metalloproteinase inhibitors that inhibit or reduce the proteolytic activity of MMPs include, but are not limited to, exogenous MMP inhibitors, batimastat (BB-94), ilomastat (GM6001), marimastat (BB2516), thiols, doxycycline, squaric acid, BB-1101, CGS-27023-A (MMI270B), COL-3 (Metastat; CMT-3), AZD3342, hydroxyurea, hydrazine, endogens, carbamyl phosphate, β -lactam, tetracycline and analogs and homologs of tetracycline, minocycline, 3- (4-phenoxybenzenesulfonyl) propylthiirane, pyrimidine-2, 4-dione, BAY12-9566, promastistat (AG-3340), N- {1S- [4- (4-chlorophenyl) piperazine-1-sulfonylmethyl ] -2-methylpropyl } -N-hydroxymethylmethyl Amide, RO 31-9790, 3- (4-phenoxybenzenesulfonylpropylthiirane, 1, 6-bis [ N' - (p-chlorophenyl) -N5-biguanidino ] hexane, tocatel, sodium 1- (12-hydroxy) octadecyl sulfate, minocycline (7-dimethylamino-6-dimethyl-6-deoxytetracycline), tetrapeptide hydroxamic acid, N- [ (2R) -2- (carboxymethyl) -4-methylpentanoyl ] -L-tryptophan- (S) -methyl-benzylamide, N- [ (2R) -2- (hydroxycarbamoylmethyl) -4-methylpentanoyl ] -L-tryptophan carboxamide, N-hydroxy-1, 3-bis- (4-methoxybenzenesulfonyl) -5, 5-dimethyl- [1,3] -piperazine-2-carboxamide, N- {1S- [4- (4-chlorophenyl) piperazine-1-sulfonylmethyl ] -2-methylpropyl } -N-hydroxyformamide, triaryl-oxy-aryloxy-pyrimidine-2, 4, 6-trione, 4r diarylbutyric acid, 5-diarylvaleric acid, fenbufen, the peptide MMPI, hydroxamic acid, tricyclic butyric acid, biphenyl butyric acid, heterocycle-substituted phenyl v-butyric acid, sulfonamide, succinamide, FN-439 (p-aminobenzoyl-Gly-Pro-D-Leu-D-Ala-NHOH, MMP-Inh-1) Sulfonated amino acids, MMP9 inhibitor I (CTK8G1150), ONO-4817, Ro 28-2653, SB-3CT, neutralizing anti-MMP antibodies, and tacrolimus (FK 506).

MMP inhibitors also include the tissue inhibitor family of MMPs (TIMPs). As used herein, the term "TIMP" refers to an endogenous tissue inhibitor of metalloproteases, which are known to be involved in physiological/biological functions, including inhibiting active matrix metalloproteases, regulating pro-MMP activation, cell growth, and regulating angiogenesis. The human "TIMP family" comprises four members: TIMP-1, TIMP-2, TIMP-3 and TIMP-4. The TIMP-1 protein is the most widely expressed and studied member of the TIMP family. Other members of the TIMP family include TIMP-2, TIMP-3 and TIMP-4. TIMP proteins not only share common structural features, including a series of conserved cysteine residues that form disulfide bonds necessary for native protein conformation (Brew et al, 2000), but they also have widely overlapping biological activities. The conserved N-terminal region of the TIMP protein is essential for functional inhibitory activity, while the distinct C-terminal region is thought to modulate the inhibitory selectivity and binding efficiency of agents for MMPs). However, in addition to their ability to act as MMP inhibitors, various TIMP family members may also exhibit additional biological activities, including proliferation and apoptosis modulation in addition to angiogenesis and inflammatory response modulation.

TIMP-1 has been found to inhibit most MMPs (except MMP-2 and MMP-14), and preferentially to inhibit MMP-8. TIMP-1 is produced and secreted in soluble form by a variety of cell types and is widely distributed throughout the body. It is a widely glycosylated protein with a molecular mass of 28.5 kDa. TIMP-1 inhibits the active form of MMP and is complexed with the native form of MMP 9. Like MMP9, TIMP-1 expression is sensitive to many factors. A wide variety of agents cause increased synthesis of TIMP-1, including: TGF β, EGF, PDGF, FGFb, PMA, all-trans Retinoic Acid (RA), IL1, and IL 11.

TIMP-2 is a 21kDa glycoprotein expressed by a variety of cell types. It forms a non-covalent stoichiometric complex with both the potential and active MMPs. TIMP-2 shows preferential inhibition of MMP-2.

TIMP-3 generally binds to the ECM and inhibits the activity of MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13. TIMP-3 showed 30% amino acid homology to TIMP-1 and 38% homology to TIMP-2. TIMP-3 has been shown to facilitate isolation of transformed cells from the ECM and to accelerate morphological changes associated with cell transformation.

TIMP-3 is unique among TIMPs due to its high affinity binding to the ECM. TIMP-3 has been shown to facilitate isolation of transformed cells from the ECM and to accelerate morphological changes associated with cell transformation. TIMP-3 comprises a glycosaminoglycan (GAG) binding domain comprising six amino acids thought to be responsible for association with the cell surface (Lys30, Lys26, Lys22, Lys42, Arg20, Lys 45). TIMP-3 is the only TIMP that normally inhibits TACE (TNF-. alpha.converting enzyme), another metalloprotease that releases soluble TNF and is responsible for processing the IL-6 receptor to play a central role in the wound healing process.

TIMP-4 inhibits all known MMPs, and preferentially inhibits MMP-2 and MMP-7. TIMP4 shows 37% amino acid identity with TIMP1 and 51% homology with TIMP2 and TIMP 3. TIMP4 is secreted extracellularly (mainly in heart and brain tissue) and acts in a tissue-specific manner for extracellular matrix (ECM) homeostasis presentation.

In some implementations, the MMP inhibitor can include a substance that can allow or enhance the MMP inhibitor's adhesion to an outer surface of a surgical stapler or component thereof, such as an outer surface of a staple (e.g., a staple leg or staple crown) or an adjunct material. The material may be an absorbable material (such as an absorbable polymer or an absorbable lubricant), which may optionally be water soluble and/or ionically charged.

Suitable absorbable polymers that may allow or enhance adhesion of MMP inhibitors to the outer surface may include synthetic and/or non-synthetic materials. Examples of non-synthetic materials include, but are not limited to, lyophilized polysaccharides, glycoproteins, bovine pericardium, collagen, gelatin, fibrin, fibrinogen, elastin, proteoglycans, keratin, albumin, hydroxyethyl cellulose, Oxidized Regenerated Cellulose (ORC), hydroxypropyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, chitin, chitosan, casein, alginate, and combinations thereof. Examples of synthetic absorbable materials include, but are not limited to, poly (lactic acid) (PLA), poly (L-lactic acid) (PLLA), Polycaprolactone (PCL), polyglycolic acid (PGA), poly (trimethylene carbonate) (TMC), polyethylene terephthalate (PET), Polyhydroxyalkanoate (PHA), copolymer of glycolide and epsilon-caprolactone (PGCL), copolymer of glycolide and trimethylene carbonate, poly (glycerol sebacate) (PGS), poly (dioxanone) (PDS), polyesters, poly (orthoesters), polyoxates, polyetheresters, polycarbonates, polyesteramides, anhydrides, polysaccharides, poly (ester-amides), tyrosine-based polyarylates, polyamines, tyrosine-based polyiminocarbonates, tyrosine-based polycarbonates, poly (D, L-lactide-urethanes), Poly (hydroxybutyrate), poly (B-hydroxybutyrate), poly (epsilon-caprolactone), polyethylene glycol (PEG), poly [ di (carboxyphenoxy) phosphazene ], poly (amino acid), pseudo poly (amino acid), absorbable polyurethane, poly (phosphazene), polyphosphazene, polyoxyalkylene, polyacrylamide, polyhydroxyethylmethacrylate, polyvinylpyrrolidone, polyvinyl alcohol, poly (caprolactone), polyacrylic acid, polyacetate, polypropylene, aliphatic polyesters, glycerol, copoly (ether-ester), polyalkylene oxalate, polyamide, poly (iminocarbonate), polyalkylene oxalate, and combinations thereof. In various embodiments, the polyester may be selected from the group consisting of polylactide, polyglycolide, trimethylene carbonate, polydioxanone, polycaprolactone, polybutylene ester, and combinations thereof.

In some embodiments, the MMP inhibitor can be absorbed into or encapsulated by a synthetic or non-synthetic absorbable polymer. In addition, the polymer can have one or more attractive surfaces associated with it that promote the adhesion of MMP inhibitor to the staple region coated with it. For example, the absorbable polymer may be porous to allow a liquid comprising the MMP inhibitor to concentrate and aggregate within the pores in which the MMP inhibitor is retained when the liquid dries. Additionally, one or both of the MMP inhibitor or the absorbable polymer can be formulated with ionic charges, thereby allowing them to be electrostatically attracted. Absorbable polymers (e.g., polyurethanes) can also be formulated to covalently attach MMP inhibitors as side chain elements to the polymer chains themselves. Finally, the water solubility of the polymer itself can be manipulated to allow the polymer and MMP inhibitor to be co-mixed before removing water from the construct to retain the drug and blended polymer.

In at least some implementations, absorbable lubricants can be used to allow or enhance the adhesion of MMP inhibitors to the outer surface of a surgical stapler or component thereof, such as the outer surface of a staple (e.g., staple leg or staple crown) or adjunct material. Suitable absorbable lubricants may include, for example, but are not limited to, any of the common tablet water insoluble lubricants such as magnesium stearate, sodium stearate, calcium stearate, powdered stearic acid, talc, paraffin, cocoa butter, graphite, lycopodium or combinations thereof. Absorbable lubricants may be derivatized fatty acids, such as stearates, e.g., magnesium stearate, sodium stearate, calcium stearate, and stearic acid.

Implantable adjunct

Various implantable appendages are provided for use in conjunction with a surgical stapling instrument. The "adjunct" is also referred to herein as "adjunct material". The adjunct can have a variety of configurations and can be formed from a variety of materials. Typically, the adjunct can be formed from one or more of a film, a foam, an injection molded thermoplastic, a vacuum thermoformed material, a fibrous structure, and mixtures thereof. The adjunct can also include one or more biologically derived materials and one or more drugs. Each of these materials is discussed in more detail below.

The adjunct can be formed of a foam, such as a closed cell foam, an open cell foam, or a sponge. An example of how such an adjunct can be made is from animal-derived collagen (such as porcine tendon) which can then be processed and lyophilized into a foam structure. Examples of various foam adjuncts are further described in the previously mentioned U.S. patent 8,393,514 entitled "Selectively Orientable Implantable Fastener Cartridge" filed on 30.9.2010.

The adjunct can also be formed of a film formed of any suitable material or combination thereof discussed below. The film may include one or more layers, each of which may have a different degradation rate. In addition, the membrane may have various regions formed therein, such as reservoirs capable of releasably retaining one or more pharmaceutical agents (e.g., at least one MMP inhibitor) therein in a number of different forms. One or more different coatings, which may include absorbable or non-absorbable polymers, may be used to seal the reservoir in which the at least one medicament is disposed. The film may be formed in various ways, for example, it may be an extruded or compression molded film.

The adjunct can also be formed from an injection molded thermoplastic material or a vacuum thermoformed material. Examples of various molded appendages are further described in U.S. patent publication 2013/0221065 entitled "fast card Comprising a releaseabaly Attached Tissue Thickness Compensator," filed on 8.2.2013, which is hereby incorporated by reference in its entirety. The adjunct may also be a fiber-based lattice, which may be a woven, knitted or nonwoven, such as a meltblown, needle punched or heat-constructed loose weave. The adjunct can have multiple regions that can be formed by the same type of compartment or different types of compartments that can be brought together to form the adjunct in a number of different ways. For example, the fibers may be woven, knitted, or otherwise interconnected to form a regular or irregular structure. The fibers may be interconnected such that the resulting adjunct is relatively loose. Alternatively, the adjunct can comprise tightly interconnected fibers. The appendage may be in the form of a sheet, tube, spiral, or any other structure that may include a flexible portion and/or a more rigid reinforcing portion. The adjunct can be configured such that certain regions thereof can have denser fibers while other regions have lower density fibers. The fiber density may vary in different directions along one or more dimensions of the adjunct, based on the intended application of the adjunct.

The adjunct can also be a hybrid construct such as a laminated composite or melt interlocked fibers. Examples of various hybrid building appendages are further described in the following patents: U.S. patent publication 2013/0146643 entitled "additive Film laboratory" filed on 8.2.2013 And U.S. patent 7,601,118 entitled "minimum active Medical immersion And Device And Method For Using The Same" filed on 12.9.2007, which are hereby incorporated by reference in their entirety.

The appendage may be formed from a variety of materials. These materials may be used in various embodiments for different purposes. These materials may be selected to facilitate tissue ingrowth in accordance with the desired treatment to be delivered to the tissue. The materials described below can be used to form the adjunct in any desired combination.

These materials may include bioabsorbable polymers and biocompatible polymers, including homopolymers and copolymers. Non-limiting examples of homopolymers and copolymers include p-dioxanone (PDO or PDS), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), Polycaprolactone (PCL), trimethylene carbonate (TMC), and polylactic acid (PLA), poly (glycolic acid-co-lactic acid) (PLA/PGA) (e.g., PLA/PGA materials for Vicryl, Vicryl rapidide, PolySorb, and Biofix), polyurethanes (such as Elastane, Biospan, Tecoflex, Bionate, and Pellethane fibers), polyorthoesters, polyanhydrides (e.g., Gliadel and Biodel polymers), polyoxoates, polyesteramides, and tyrosine-based polyesteramides. The copolymer can also include poly (lactic acid-co-polycaprolactone) (PLA/PCL), poly (L-lactic acid-co-polycaprolactone) (PLLA/PCL), poly (glycolic acid-co-trimethylene carbonate) (PGA/TMC) (e.g., Maxon), poly (glycolic acid-co-caprolactone) (PCL/PGA) (e.g., Monocryl and caprly), PDS/PGA/TMC (e.g., Biosyn), PDS/PLA, PGA/PCL/TMC/PLA (e.g., Caprosyn), and LPLA/DLPLA (e.g., Optima).

The adjunct described herein is capable of releasably retaining therein at least one medicant, which can be selected from a large number of different medicants. Agents include, but are not limited to, any of the MMP inhibitors disclosed herein.

Other agents for use with the adjunct include, but are not limited to, for example, antimicrobial agents (such as antibacterial and antibiotic agents), antifungal agents, antiviral agents, anti-inflammatory agents, growth factors, analgesics, anesthetics, tissue matrix degeneration inhibitors, anticancer agents, hemostatic agents, and other agents that elicit a biological response.

The adjunct can also include other active agents, such as active cell cultures (e.g., diced autologous tissue), agents for stem cell therapy (e.g., biostures and Cellerix s.l.), hemostatic agents, and tissue healing agents. Non-limiting examples of hemostatic agents may include cellulose (such as Oxidized Regenerated Cellulose (ORC) (e.g., Surgicel and interrupted)), fibrin/Thrombin (e.g., Thrombin-JMI, TachoSil, Tiseel, Floseal, Evicel, TachoComb, Vivostat, and Everest), autologous platelet plasma, gelatin (e.g., Gelfilm and Gelfoam), hyaluronic acid (such as microfibers (e.g., yarns and textiles)), or other structures based on hyaluronic acid or hydrogels based on hyaluronic acid. The hemostatic agent may also include a polymeric sealant such as, for example, bovine serum albumin and glutaraldehyde, human serum albumin and polyethylene crosslinkers, and ethylene glycol and trimethylene carbonate. The polymeric sealant may comprise a FocalSeal surgical sealant developed by Focal inc.

Non-limiting examples of antimicrobial agents include ionic silver, aminoglycosides, streptomycin, polypeptides, bacitracin, triclosan, tetracyclines, doxycycline, minocycline, demeclocycline, tetracycline, oxytetracycline, chloramphenicol, nitrofurans, furazolidone, nitrofurantoin, beta-lactam, penicillin, amoxicillin + clavulanic acid, azlocillin, flucloxacillin, ticarcillin, piperacillin + tazobactam, trogopacin, Biopiper TZ, Zosyn, carbapenems, imipenem, meropenem, ertapenem, doripenem, biapenem, panipenem/betamipron, quinolones, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, sulfonamides, sulfamylon, sulfacetamide, sulfadiazinon, sulfacetamide, sulfadiazinon, silver sulfadiazine, sulfadimidine, sulfamethoxazole, sulfasalazine, sulfisoxazole, compound sulfamethoxazole, Arthromycin, geldanamycin, herbimycin, fidaxomicin, glycopeptide, teicoplanin, vancomycin, telavancin, dalbavancin, Oritazanin, lincosamides, clindamycin, lincomycin, lipopeptide, daptomycin, macrolides, azithromycin, clarithromycin, erythromycin, roxithromycin, telithromycin, spiramycin, oxazolidinone, linezolid, aminoglycosides, amikacin, gentamycin, kanamycin, neomycin, netilmicin, tobramycin, Paromomycin (Paromycin), cephalosporins, cephapirin, ceftarozam, cefaclor, flomoxef, monobactam, aztreonam, colistin, and polymyxin B.

Non-limiting examples of antifungal agents include triclosan, polyenes, amphotericin B, candida, felpine, hamycin, natamycin, nystatin, rimocidin, azoles, imidazoles, triazoles, thiazoles, allylamines, amorolfine, butenafine, naftifine, terbinafine, echinocandins, anidulafungin, caspofungin, micafungin, ciclopirox, and benzoic acid.

Non-limiting examples of antiviral agents include: uncoating inhibitors such as, for example, amantadine, rimantadine, Pleconaril; reverse transcriptase inhibitors such as, for example, acyclovir, lamivudine, Antisense drugs (Antisense), fomivirsen, morpholino compounds, ribozymes, rifampin; and virucides such as, for example, cyanobacterial antiviral protein-N (Cyanovirin-N), Griffithsin, Scytovirin, alpha-lauroyl-L-arginine ethyl ester (LAE), and ionic silver.

Non-limiting examples of anti-inflammatory agents include non-steroidal anti-inflammatory agents (e.g., salicylates, aspirin, diflunisal, propionic acid derivatives, ibuprofen, naproxen, fenoprofen, and loxoprofen), acetic acid derivatives (e.g., tolmetin, sulindac, and diclofenac sodium), enolic acid derivatives (e.g., piroxicam, meloxicam, droxicam, and lornoxicam), anthranilic acid derivatives (e.g., mefenamic acid, meclofenamic acid, and flufenamic acid), selective COX-2 inhibitors (e.g., celecoxib (celecoxib), parecoxib, rofecoxib (vancomycin), sulfonylanilide, nimesulide, and lonicerasin), immunoselective anti-inflammatory derivatives, corticosteroids (e.g., dexamethasone), and iNOS inhibitors.

Non-limiting examples of growth factors include those that stimulate cell growth, healing, remodeling, proliferation and differentiation. Exemplary growth factors may be short-range (paracrine), long-range (endocrine), or self-stimulatory (autocrine). Other examples of growth factors include growth hormones (e.g., recombinant growth factors, Nutropin, Humatrope, Genotropin, Norditropin, Saizen, Omnitirope, and biosynthetic growth factors), Epidermal Growth Factors (EGF) (e.g., inhibitors, gefitinib, erlotinib, afatinib, and cetuximab), heparin-binding EGF-like growth factors (e.g., epidermal regulin, cytokines, amphiregulin, and Epigen), transforming growth factor alpha (TGF-a), neurotonin 1-4, Fibroblast Growth Factors (FGF) (e.g., FGF1-2, FGF2, FGF11-14, FGF18, FGF15/19, FGF21, FGF23, FGF7, or Keratinocyte Growth Factor (KGF), FGF10 or KGF2, and phenytoin), insulin-like growth factors (IGF) (e.g., IGF-1, IGF-2, and platelet-derived growth factor (PDGF)), vascular growth factors (VEGF) (e.g., endothelial growth factor (VEGF), inhibitors, bevacizumab, ranibizumab, VEGF-A, VEGF-B, VEGF-C, VEGF-D, and bevacplemine).

Additional non-limiting examples of growth factors include cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) (e.g., inhibitors that inhibit inflammatory responses, and GM-CSF that has been made using recombinant DNA technology and via recombinant yeast sources), granulocyte colony-stimulating factor (G-CSF) (e.g., filgrastim, leguminosin, and Youjin), tissue growth factor beta (TGF-B), leptin, and Interleukin (IL) (e.g., IL-1a, IL-1B, conatin, IL-2, aldesleukin, Interking, dien interleukin, IL-3, IL-6, IL-8, IL-10, IL-11, and Omepleren interleukin). Non-limiting examples of growth factors also include erythropoietins (e.g., dabecoptin, epocet, Dynepo, Epomax, betaepoetin, Silapo, and Retacrit).

Non-limiting examples of analgesics include narcotics, opioids, morphine, codeine, oxycodone, hydrocodone, buprenorphine, tramadol, non-narcotics, paracetamol, acetaminophen, non-steroidal anti-inflammatory drugs, and flupirtine.

Non-limiting examples of anesthetics include local anesthetics (e.g., lidocaine, benzocaine, and ropivacaine) and general anesthetics.

Non-limiting examples of anti-cancer agents include monoclonal antibodies, bevacizumab (avastin), cellular/chemoattractants, alkylating agents (e.g., bifunctional cyclophosphamide, nitrogen mustard, chlorambucil, melphalan, monofunctional nitrosoureas and temozolomide), anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone and valrubicin), cytoskeletal disrupters (e.g., paclitaxel and docetaxel), epothilone agents that restrict cell division by inhibiting microtubule function, inhibitors of various enzymes required to block cell division or certain cell functions, histone deacetylase inhibitors (e.g., Vorinostat and Romidecasin), topoisomerase I inhibitors (e.g., irinotecan and topotecan), topoisomerase II inhibitors (e.g., etoposide, Evoxil ®), topoisomerase II inhibitors (e.g., Etoposide, Tebucin: (e), Tebuconazole ®, and Tebuconazole @, etc.), and combinations thereof, Teniposide and Tafluposide), kinase inhibitors (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and Vismodegib), nucleotide analogs (e.g., azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, 5-FU, Adrucil, Carac, Efudix, Efudex, fluroprolex, gemcitabine, hydroxyurea, mercaptopurine, and thioguanine), peptide antibiotic agents that cleave DNA and disrupt DNA unwinding/winding (e.g., bleomycin and actinomycin), platinum-based antineoplastic agents that crosslink DNA that inhibit DNA repair and/or synthesis (e.g., carboplatin, cisplatin, oxaliplatin, and lenacil), retinoids (e.g., tretinoin, alitretinoids, and saxarotene), vinca biological agents that inhibit mitosis and microtubule formation (e.g., vinblastine, vincristine), vincristine, Vindesine, vinorelbine), anti-intestinal-infarction agents, prokinetic agents, immunosuppressive agents (e.g., tacrolimus), hematologic modifiers (e.g., vasodilators, viagra, and nifedipine), 3-hydroxy-3-methyl-glutaryl-coa (hmg coa) reductase inhibitors (e.g., atorvastatin), and anti-angiogenic agents.

Exemplary medicaments also include agents that passively aid in wound healing, such as nutrients, oxygen scavengers, amino acids, collagen synthesizers, glutamine, insulin, butyrate, and dextran. Exemplary agents also include anti-adhesion agents, non-limiting examples of which include hyaluronic acid/carboxymethylcellulose (seprafilm), oxidized regenerated cellulose (interleaved), and 4% icodextrin (extra, Adept).

Adjuncts according to the technology can be associated with at least one agent (e.g., an MMP inhibitor) in a number of different ways in order to provide a desired effect in a desired manner, such as on tissue ingrowth. The at least one medicant can be configured to be released from the adjunct in a plurality of spatial and temporal patterns to trigger a desired healing process at the treatment site. The agent can be disposed in, associated with, incorporated in, dispersed in, or otherwise associated with the adjunct. For example, the adjunct can have one or more regions in which one or more different medicants can be releasably retained. These regions may be other different or continuous regions within different reservoirs or appendages of various sizes and shapes and holding medicament therein in various ways. In some aspects, the particular configuration of the adjunct allows it to releasably retain one medicant or more than one different medicants therein.

Regardless of the manner in which the agents are disposed within the adjunct, an effective amount of at least one agent can be encapsulated within a container, such as a pellet, which can be in the form of a microcapsule, a microbead, or any other container. The container may be formed from a bioabsorbable polymer.

Targeted delivery and release of at least one medicant from an adjunct can be accomplished in a variety of ways depending on various factors. Typically, the at least one medicant can be released from the adjunct material in a dosage form such that the medicant is released substantially immediately upon delivery of the adjunct material to the tissue. Alternatively, the at least one medicant can be released from the adjunct over a duration of time, which can be minutes, hours, days, or longer. The rate of timed release and the amount of agent released may depend on various factors such as the rate of degradation of the region from which the agent is released, the rate of degradation of one or more coatings or other structures used to retain the agent in the adjunct, the environmental conditions at the treatment site, and various other factors. In some aspects, when the adjunct has more than one medicant disposed therein, the dose release of the first medicant can regulate the release of the second medicant that begins to be released after the release of the first medicant. The adjunct can include a plurality of medicants, each of which can affect the release of one or more other medicants in any suitable manner.

The release of the at least one medicant in a dosage form or timed release can occur or begin substantially immediately after delivery of the adjunct material to the tissue, or can be delayed for a predetermined time. The delay may depend on the structure and nature of the adjunct or one or more regions thereof.

Temporary inhibition of wound healing

In a further aspect, provided herein is a method for temporarily inhibiting wound healing at a surgical site following surgical stapling of tissue with a surgical stapler. The method can include attaching an adjunct material to an end effector of a surgical stapler; engaging tissue between a cartridge assembly of an end effector and an anvil; and actuating the end effector to eject the staples from the cartridge assembly into tissue. The staples extend through the adjunct material to retain the adjunct material at the surgical site. At least one of a portion of the plurality of staples (e.g., staple legs and/or staple crowns) and/or adjunct material can include a releasably effective amount of at least one MMP inhibitor. As used herein, the term "effective amount" with respect to MMP inhibitor released according to the devices and methods herein refers to an amount of MMP inhibitor sufficient to inhibit at least one MMP to an extent such that the tissue strength increases within 1-4 days following tissue stapling. Release of MMP inhibitors in tissue at the suture site prevents MMP-mediated extracellular matrix degeneration during wound healing in the tissue in a predetermined manner. In addition, release of MMP inhibitors at the suture site can inhibit inflammation at the wound site, thereby reducing invasion of immune cells (such as macrophages, neutrophils, or T cells) that otherwise occur during the inflammatory phase of wound healing.

In some implementations, the MMP inhibitor can be configured to be released from the staples and/or adjunct material and into surrounding tissue two to three days after staple insertion. For example, the MMP inhibitor can be encapsulated in a resorbable polymer (such as any of the resorbable polymers disclosed herein) that begins to disintegrate and release its contents about 48 hours after insertion of the staples into the tissue, and continues for about the next 24-36 hours (such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 hours).

A sufficient amount of MMP inhibitor can be released from the plurality of staples and/or the adjunct material to inhibit at least five percent (such as inhibit any of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) of the proteolytic activity of the one or more MMP inhibitors expressed at the tissue stapling site immediately following staple insertion (such as those MMP inhibitors expressed within 1-4 days after tissue stapling, e.g., MMP1, MMP2, MMP8, and/or MMP 9). In some embodiments, a sufficient amount of the MMP inhibitor is released from the plurality of staples and/or adjunct material upon insertion of the staples into tissue to ensure a concentration of the MMP inhibitor in the wound site surrounding the staples of at least about 0.1nM to about 500 μ Μ, such as any one of: about 0.1nM, 0.2nM, 0.3nM, 0.4nM, 0.5nM, 0.6nM, 0.7nM, 0.8nM, 0.9nM, 1nM, 2nM, 3nM, 4nM, 5nM, 6nM, 7nM, 8v, 9nM, 10nM, 11nM, 12nM, 13nM, 14nM, 15nM, 1nM6nM, 17nM, 18nM, 19nM, 20nM, 21nM, 22nM, 23nM, 24nM, 25nM, 30nM, 35nM, 40nM, 45nM, 50nM, 55nM, 60nM, 65nM, 70nM, 75nM, 80nM, 85nM, 90nM, 95nM, 100nM, 200nM, 300nM, 400nM, 500nM, 600nM, 700nM, 800nM, 900nM, 1. mu M, 2. mu.M, 3. mu.M, 4. mu.M, 5. mu.M, 10. M, 15nM, 20. mu.M, 20. M, 400nM, 500nM, 600nM, 700nM, 800nM, 900nM, 1. mu.M, 2. mu.M, 3. mu.M, 4. mu.M, 5. mu.M, 10M, 65, 70M, 75nM, 75M, 75nM, 600nM, 75nM, 600M, 75nM, 60M, 75nM, 60M, 75nM, 70M, 60M, 75nM, 70nM, 75nM, 50M, 75nM, 60nM, 50nM, 60nM, 70nM, 50M, 60M, 70nM, 60M, 70nM, 60M, 60nM, 70M, 60M, 70nM, 70M, 60M, 70nM, 70M, 60M, 70M, 60nM, 70M, 60nM, 70M, 60nM, 70M, 70nM, 60nM, 70M, 1, 70M, 75nM, 70M, 75nM, 600nM, 60M, 60nM, 70M, 600nM, 60M, 600nM, 75nM, 600, 70M, 75nM, 600nM, MMP inhibitor in a wound site of 95. mu.M, 100. mu.M, 125. mu.M, 150. mu.M, 175. mu.M, 200. mu.M, 225. mu.M, 250. mu.M, 275. mu.M, 300. mu.M, 325. mu.M, 350. mu.M, 375. mu.M, 400. mu.M, 425. mu.M, 450. mu.M, 475. mu.M, or 500. mu.M or more, including values falling between these values.

In further implementations, releasing MMP inhibitor from a plurality of staples and/or adjunct material after insertion of the staples into tissue increases the strength of the tissue at the wound site due to increased production and retention of collagen fibers in the ECM immediately surrounding the staple insertion site. In some embodiments, the tissue surrounding the staples and/or adjunct material releasably coated with at least one MMP inhibitor comprises at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% or more increased collagen compared to the tissue surrounding the staples and/or adjunct material non-releasably coated with at least one MMP inhibitor.

Following insertion of the pin, the surrounding cells of the clot release inflammatory cytokines and growth factors, which attract a variety of cells to the wound site. Specifically, following tissue injury, macrophages and neutrophils are stimulated to produce Reactive Oxygen Species (ROS) and MMPs (e.g., MMP2, MMP8, and/or MMP9) to promote cell adhesion and ECM remodeling. For example, during enhanced keratinocyte migration in wound healing, expression of MMP2 coincides with expression of laminin-332. Since both MMP2 and MMP9 can cleave the γ -2 chain of laminin-322, they produce proto-migratory and EGF-like fragments that bind EGF receptors to trigger cell migration of keratinocytes at the wound matrix.

During the inflammatory phase of wound healing, fibronectin and other ECM protein fragments may attract monocytes from the blood stream to the wound site. The interaction at the wound site results in differentiation of monocytes into macrophages, which are stimulated by growth factors to produce ROS, MMPs, and various growth factors such as Platelet Derived Growth Factor (PDGF), transforming growth factor-beta (TGF-beta), Vascular Endothelial Growth Factor (VEGF), and Fibroblast Growth Factor (FGF). One factor that can stimulate macrophages is angiotensin ii (angii). The Renin Angiotensin System (RAS) is a pathway that regulates angiotensin (a hormone peptide) to ultimately produce the major effector, AngII. The effector is present in macrophages, neutrophils, fibroblasts and endothelial cells. Upon binding and stimulation by AngII, inflammatory cells such as macrophages produce ROS and MMPs, which subsequently promote migration and proliferation of keratinocytes and other pro-inflammatory wound cells.

Thus, in some aspects, a sufficient amount of MMP inhibitor is released from a plurality of staples and/or adjunct material to prevent or reduce the invasion of one or more pro-inflammatory immune cells (such as macrophages, neutrophils, or T cells) into the wound surrounding the staple insertion site (such as any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%). In addition, a sufficient amount of MMP inhibitor is released from the plurality of staples and/or adjunct materials to prevent or reduce (such as any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) expression of one or more proinflammatory substances or enzymes (such as, for example, one or more of ROS, PDGF, TGF- β, VEGF, FGF or AngII) at the wound site.

In another embodiment, a sufficient amount of one or more MMP inhibitors are released from the peg and/or adjunct material to prevent or reduce collagen degradation in the ECM within 1 to 4 days (such as any of 1, 2, 3, or 4 days) after peg insertion. For example, use of an MMP inhibitor in accordance with the surgical stapling apparatus and methods disclosed herein can cause 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% less degradation of collagen in the ECM immediately surrounding the staple insertion site relative to the amount of ECM collagen degradation that would otherwise occur in the absence of the one or more MMP inhibitors.

Those skilled in the art will appreciate that the present invention has application in conventional minimally invasive and open surgical instruments, as well as in robotic-assisted surgery.

The device disclosed herein may be designed to be disposed of after a single use, or it may be designed to be used multiple times. In either case, however, the device may be reconditioned for reuse after at least one use. Refurbishment may include any combination of disassembly of the device, followed by cleaning or replacement of particular parts, and subsequent reassembly steps. In particular, the device may be disassembled, and any number of the particular pieces or parts of the device may be selectively replaced or removed in any combination. After cleaning and/or replacement of particular components, the device may be reassembled for subsequent use either at a reconditioning facility, or by a surgical team immediately prior to a surgical procedure. Those skilled in the art will appreciate that the finishing assembly may be disassembled, cleaned/replaced, and reassembled using a variety of techniques. The use of such techniques and the resulting prosthetic devices are within the scope of the present application.

Additional exemplary structures and components are described in U.S. application ______ [ 47364-.

Those skilled in the art will recognize additional features and advantages of the present invention in light of the above-described embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety.

Claims (9)

1. A staple cartridge assembly for use with a surgical stapler, comprising:

a cartridge body having a plurality of staple cavities, each staple cavity having one of a plurality of surgical staples disposed therein; and is

Wherein at least one of a portion of the plurality of staples comprises an effective amount of at least one Matrix Metalloproteinase (MMP) inhibitor effective to prevent MMP-mediated at least one of extracellular matrix degeneration and inflammation during healing of the wound in the tissue in a predetermined manner;

The at least one MMP inhibitor is disposed on at least a portion of the plurality of staples,

wherein the at least one MMP inhibitor comprises a substance configured to allow or enhance MMP inhibitor adhesion to an outer surface of the peg;

wherein the substance is an absorbable polymer, and wherein the absorbable polymer is porous, and wherein the at least one MMP inhibitor and the absorbable polymer are formulated with an ionic charge, thereby allowing electrostatic attraction thereof.

2. The assembly of claim 1, further comprising a biocompatible adjunct material releasably retained on the cartridge body and configured to be delivered to tissue by deployment of the staples in the cartridge body, wherein an effective amount of at least one MMP inhibitor is disposed within the adjunct material and releasable therefrom.

3. The assembly of claim 1, wherein the MMP inhibitor is configured to inhibit one or more of: MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP23A, MMP23B, MMP25, MMP26, MMP27, and MMP 28.

4. The assembly of claim 3, wherein the MMP inhibitor is configured to inhibit collagenase, gelatinase, stromelysin, or membrane-type MMPs.

5. The assembly of claim 1, wherein the MMP inhibitor is configured to inhibit MMP 9.

6. The assembly of claim 1, wherein the MMP inhibitor is a Tissue Inhibitor of Metalloproteases (TIMP).

7. The assembly of claim 6, wherein the TIMP is at least one of TIMP1, TIMP2, TIMP3, and TIMP 4.

8. The assembly of claim 1, wherein the MMP inhibitor is one or more of: hydroxy acid salts, carboxylic acid salts, carbamoylphosphonic acid salts, hydroxyurea, hydrazine, beta-lactams, squaric acid, nitrogen-containing ligands, and thiols.

9. The assembly of claim 1, wherein the MMP inhibitor is configured to prevent inflammatory cells from being attracted to the tissue after deployment of the staples.

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