CN110740764B - Surgical fasteners with broad spectrum MMP inhibitors - 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 one broad-spectrum Matrix Metalloproteinase (MMP) inhibitor effective to prevent MMP-mediated extracellular matrix degeneration during wound healing in tissue.

Description

Surgical fasteners with broad spectrum MMP inhibitors

Technical Field

The present invention provides surgical instruments and methods having a broad spectrum of MMP inhibitors.

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 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 having at least one releasable broad-spectrum Matrix Metalloproteinase (MMP) inhibitor for delivery to tissue surrounding a 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 has a surgical staple disposed therein. The cartridge body can further comprise a biocompatible adjunct material releasably retained thereon and configured to be delivered to tissue by deployment of staples in the cartridge body. The cartridge assembly may also have an effective amount of at least one broad-spectrum Matrix Metalloproteinase (MMP) inhibitor effective to prevent MMP-mediated degeneration of the extracellular matrix during healing of the wound in a predetermined manner in the tissue.

In one embodiment, the at least one broad spectrum 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, and the crown of the plurality of staples. In other aspects, an effective amount of at least one broad spectrum MMP inhibitor can be disposed within and releasable from the adjunct material. The broad spectrum MMP inhibitor can inhibit at least five of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP 16. The MMP inhibitor may be an anti-inflammatory agent, for example GM6001 (ilomastat), or may be a tetracycline antibiotic, for example doxycycline or minocycline. The broad-spectrum MMP inhibitor may also be at least one of remasterstat, batimastat (BB-94), BB-1101, CGS-27023-A, marimastat, ONO-4817, Ro28-2653, and SB-3 CT. The MMP inhibitor can inhibit four or less of MMP1, MMP2, MMP3, MMP9, MMP9, MMP12, MMP13, MMP14, and MMP16, and can be at least one of MMI-166, tanostat, ceromastat, MMI-270, ABT-770, Premastat, tetrahydropyran, RS-130830, and 239796-97-5. The MMP inhibitor can be encapsulated by an absorbable polymer on a plurality of staples or adjunct materials, or can be attached as a side chain molecule to an adjunct material.

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, the biocompatible adjunct material configured to be delivered to tissue by deployment of staples in the cartridge body. The end effector may further include an effective amount of at least one broad-spectrum Matrix Metalloproteinase (MMP) inhibitor effective to prevent MMP-mediated extracellular matrix degeneration during healing of the wound in the tissue in a predetermined manner.

In another aspect, provided herein is a method for temporarily inhibiting wound healing at a surgical site immediately after surgical stapling of tissue by a surgical stapler. The method includes 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 the adjunct material can include an effective amount of at least one broad-spectrum Matrix Metalloproteinase (MMP) inhibitor, and release of the MMP inhibitor can prevent MMP-mediated extracellular matrix degeneration during healing of the wound in the tissue in a predetermined manner.

In one embodiment, the MMP inhibitor used in any of the devices or methods disclosed herein can inhibit at least five of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16, and can be at least one of remmastat, batimastat (BB-94), doxycycline, minocycline, GM6001 (ilomastat), and BB-1101, CGS-27023-a, marimastat, ONO-4817, Ro 28-2653, and SB-3 CT. The MMP inhibitor may be released immediately upon delivery to the tissue, or release may be delayed for hours or up to 1 day, 2 days, or 3 days. In other aspects, the MMP inhibitor can inhibit four or less of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16, and can be at least one of MMI-166, tanostat, cimastat, MMI-270, ABT-770, pramestat, tetrahydropyran, RS-130830, and 239796-97-5. In some aspects, the tissue may be colon tissue, such as colon tissue performed immediately after a surgical resection.

Drawings

The present invention will be more fully understood from the detailed description given hereinbelow with reference to 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 a 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; and is

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 stages of wound healing involves different aspects of the healing process, these stages 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 generally affects the rate of overall wound healing and, therefore, generally 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 rate of overall wound healing and the overall recovery of the patient.

Matrix Metalloproteinases (MMPs) are a family of proteases that break down 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.

Immediately after 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 phase of wound healing. However, without being bound by theory, it is believed that this natural process may at least initially (i.e., up to about three days after staple insertion) cause the tissue surrounding the staple site to weaken, thereby rendering it susceptible to tears 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) immediately after 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.

Previous studies have shown that various MMPs cause immediate degradation of ECM following tissue suturing (see, e.g., Stumpf et al, 2005, Surgery 137: 229-234 and passternak et al, 2010, color Dis 12: e 93-e 98). Accordingly, it would be desirable to use one or more broad-spectrum 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. Without being bound by theory, by preventing native MMP-mediated degradation of the ECM immediately following staple insertion, a broad spectrum MMP inhibitor may be able to prevent tissue leakage complications associated with tissue stapling by strengthening the tissue surrounding the wound site. In some cases, a broad spectrum of MMP inhibitors provided by the device 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.) occurring 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 using MMP inhibitors in wound healing can be found in the following documents: argen et al, Surgery,2006,140 (1: 72-82; krarup et al, Int JColorectal 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; deHingh et al, int.j.color.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 may 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 linear surgical stapler 10 suitable for use with one or more appendages and/or one or more medicants. The stapler 10 generally includes a handle assembly 12, a shaft 14 extending distally from a distal end 12d of the handle assembly 12, and an end effector 30 located at the distal end 14d of the shaft 14. The end effector 30 has opposed lower and upper jaws 32, 34, although other types of end effectors may be used with the shaft 14, handle assembly 12, and components associated therewith. Lower jaw 32 has a staple channel 56 configured to support staple 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 the end 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 the end 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 the end 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 the instrument 10. For example, the handle assembly 12 can include a knob 26 mounted adjacent its distal end 12d that can facilitate rotation of the shaft 14 and/or the end effector 30 about the longitudinal axis L of the shaft 14 relative to the handle assembly 12. The handle assembly 12 can further include a clamping component as part of a clamping system actuated by the clamping trigger 22 and a firing component as part of a firing system actuated by the firing trigger 24. The clamping trigger 22 and the firing trigger 24 may be biased to an open position relative to the stationary handle 20, such as by torsion springs. Movement of the clamping trigger 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 firing trigger 24 may actuate a firing system, which, as described below, may eject staples from a staple 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 embodied end 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. A staple 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 the staple cartridge 40. Although in the illustrated implementation, the upper jaw 34 has a proximal pivot end 34p only distally of its engagement with the shaft 14 that is pivotally received within the proximal end 56p of the staple 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 opposing staple 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 pivoting end 34p of the upper jaw 34 includes a closure feature 34c distal to its pivotal attachment to the staple channel 56. Thus, in response to the clamping trigger 22, the closure tube 46 selectively imparts an opening motion to the upper jaw 34 during proximal longitudinal movement of the closure 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 described above, in various implementations, opening and closing of the end 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 the shaft 14, e.g., in a longitudinal firing bar slot 14s of the shaft 14, and is guided by the firing motion from the handle 12. Actuation of the firing trigger 24 may affect distal motion of the E-beam 38 through at least a portion of the end effector 30 to thereby cause firing of staples contained within the staple 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 the staple cartridge 40. The upward movement of the staple drivers 48 applies an upward force to each of the plurality of staples within the cartridge 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 the staple 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 the end 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 the surgical stapler 10. Features of the stapler 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 clamping trigger 22 may be pulled toward the stationary handle 20 to actuate the clamping system. The trigger 22 may operate components of the clamping system such that the closure tube 46 is advanced distally through at least a portion of the shaft 14 to cause at least one of the jaws 32, 34 to collapse toward the other to clamp tissue disposed therebetween. The trigger 24 can then be pulled toward the stationary 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 the end 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 the surgical 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 opposing jaws 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 to linear staplers 10, 50 of FIGS. 1 and 4, but with some features adapted for its function as a circular stapler. Similar to the surgical 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.

The handle assembly 82 of the stapler 80 may have various actuators disposed thereon that are capable of controlling 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 of surgical 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 related 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 introduction Materials and Method of Using the Same" filed on 8.11.11.2013, U.S. patent publication 2015/0133995 entitled "Hybrid incorporated Materials for Use in surgery marking" filed on 8.11.2014, U.S. patent application 14/226,142 entitled "Surgical Instrument combining a Sensor" filed on 26.3.2014, and U.S. patent application 14/300,954 entitled "attachment Materials and Method of Using the Same" 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).

A "broad spectrum MMP inhibitor" is any compound that inhibits the proteolytic activity of more than one MMP (such as 2, 3, 4, 5, 6, 7, 8, 9 or more MMPs) by at least 5% (such as inhibiting 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). Broad spectrum MMP inhibitors are used primarily in the treatment of cancer due to the known role of MMPs in promoting cancer progression. Although preclinical studies using these inhibitors indicate that they have great potential as anticancer agents, most clinical studies fail to show efficacy as anticancer drugs (see, e.g., vandenbrouche et al, 2014, Nature rev. In some embodiments, the broad spectrum MMP inhibitor inhibits at least one of MMP8, MMP9, and/or MMP 13.

In some implementations, a broad-spectrum MMP inhibitor for use in the methods and devices disclosed herein inhibits at least 5 MMPs (such as any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more MMPs; or such as 5 or more of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP 16). One example of a broad spectrum MMP inhibitor suitable for use in the surgical stapler apparatus disclosed herein is batimastat (BB-94):

Batimastat was originally developed as an anti-cancer drug and belongs to a family of drugs known as angiogenesis inhibitors. Batamistat IC capable of being adjusted to 3nM₅₀Inhibition of MMP1 with an IC of 4nM₅₀Inhibition of MMP2 with an IC of 20nM₅₀Inhibition of MMP3 with an IC of 6nM₅₀Inhibition of MMP7 with an IC of 10nM₅₀Inhibition of MMP8, and IC at 1nM₅₀Inhibit MMP 9.

Another example of a broad spectrum MMP inhibitor for use in the methods and apparatus disclosed herein is BB-1101:

BB-1101 IC may be 8nM₅₀Inhibition of MMP1 with an IC of 4nM₅₀Inhibition of MMP2 with an IC of 30nM₅₀Inhibition of MMP3 with an IC of 60nM₅₀Inhibition of MMP7 with an IC of 3nM₅₀Inhibition of MMP8 with an IC of 3nM₅₀Inhibition of MMP9 with an IC of 5nM₅₀Inhibition of MMP12 at 7nMIC of₅₀Inhibition of MMP13, and an IC of 10nM₅₀Inhibit MMP 14.

CGS-27023-A (MMI270B) is another non-limiting example of a broad-spectrum MMP inhibitor suitable for use in the methods and apparatus disclosed herein:

CGS-27023-A may have an IC of 33nM₅₀Inhibition of MMP1 with an IC of 20nM₅₀Inhibition of MMP2 with an IC of 43nM₅₀Inhibition of MMP3 with an IC of 8nM₅₀Inhibition of MMP8 with an IC of 8nM₅₀Inhibition of MMP9, and IC at 6nM₅₀Inhibit MMP 13.

Another example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is doxycycline:

tetracycline antibiotics such as doxycycline have innate MMP inhibitory capacity. In addition, the tetracycline analogue doxycycline hyclate is indicated for periodontal disease and is the only collagenase inhibitor approved by the U.S. food and drug administration for use in any human disease (Sorsa et al, ann. med.38, 306-321 (2006)). Recent evidence suggests a role for bacteria in the wound healing process, especially on intestinal tissue after surgical excision (Boasmans et al, BMC Gastroenterology,2015, 15: 180). For example, it has been shown that deadly bacteria with high collagenase activity can lead to nail failure. Thus, antibiotics such as doxycycline can be used not only to inhibit a variety of MMPs, but also to kill collagenase-secreting bacteria that may be attracted to the wound site. Doxycycline can >IC of 400. mu.M₅₀Inhibition of MMP1 at 56 μ M IC₅₀Inhibition of MMP2 at 32 μ M IC₅₀Inhibition of MMP3 at 28 μ M IC₅₀Inhibit MMP7 at an IC of 26 μ M to 50 μ M₅₀Inhibit MMP8, and an IC of 2 μ M to 50 μ M₅₀Inhibit MMP 13.

Another non-limiting example of a broad spectrum MMP inhibitor for use in the methods and apparatus disclosed herein is GM6001 (ilomastat):

GM6001 is a member of the hydroxamic acid class of reversible metallopeptidase inhibitors. The anionic state of the hydroxamic acid group in this molecule forms a bidentate complex with the active site zinc in MMPs, thereby inhibiting MMP function. GM6001 may have an IC of 0.4nM₅₀Inhibition of MMP1 with an IC of 0.4nM₅₀Inhibition of MMP2 with an IC of 27nM₅₀Inhibition of MMP3 with an IC of 0.1nM₅₀Inhibition of MMP8 with an IC of 0.2nM₅₀Inhibition of MMP9, and an IC of 5.2nM₅₀Inhibit MMP 14.

Another example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is marimastat (BB-2516):

marimastat is a proposed anti-tumour agent developed by biotechnology companies in the uk which performs poorly in clinical trials for the treatment of cancer. Marimastat IC 5nM₅₀Inhibition of MMP1 with an IC of 6nM₅₀Inhibition of MMP2 with an IC of 200nM₅₀Inhibition of MMP3 with an IC of 20nM₅₀Inhibition of MMP7 with an IC of 2nM ₅₀Inhibition of MMP8, IC at 3nM₅₀Inhibition of MMP9, and an IC of 1.8nM₅₀Inhibits MMP 14.

Minocycline is another non-limiting example of a broad-spectrum MMP inhibitor suitable for use with the methods and devices disclosed herein:

minocycline can have an IC of 290 μ M₅₀Inhibition of MMP3 at 125 μ M IC₅₀Inhibition of MMP7 at an IC of 180. mu.M₅₀Inhibit MMP 9. Minocycline has also been shown to be effective in inhibiting MMP1 and MMP 2.

Another example of a broad spectrum MMP inhibitor for use in the methods and apparatus disclosed herein is ONO-4817:

ONO-4817 IC at 1.6nM₅₀Inhibition of MMP1 with a K of 0.73nM_iInhibition of MMP2 with a K of 42nM_iInhibition of MMP3 with a K of 2.5nM_iInhibition of MMP7 with a K of 1.1nM_iInhibition of MMP8 with an IC of 2.1nM₅₀Inhibition of MMP9 with a K of 0.45nM_iInhibition of MMP12, and at a K of 1.1nM_iInhibit MMP 13.

Another example of a broad spectrum MMP inhibitor for use in the methods and apparatus disclosed herein is Ro 28-2653:

ro28-2653 can have an IC of 7nM to 246nM₅₀Inhibition of MMP2 with an IC of 15nM₅₀Inhibition of MMP8 with an IC of 12nM to 23nM₅₀Inhibition of MMP9 with an IC of 96nM₅₀Inhibition of MMP14, and IC at 91nM₅₀Inhibit MMP 16.

SB-3CT is another non-limiting example of a broad-spectrum MMP inhibitor for use in the methods and devices disclosed herein:

SB-3CT can be 206. mu.M K_iInhibition of MMP1 with a K of 14nM_iInhibition of MMP2 with a K of 15nM_iInhibition of MMP3 at 96. mu.M K_iInhibition of MMP7 with a K of 1.1nM_iInhibition of MMP8, and IC at 600nM₅₀Inhibit MMP 9.

Remasistat (Bms-275291) is another non-limiting example of a broad-spectrum MMP inhibitor suitable for use with the methods and devices disclosed herein:

remacestat is a broad spectrum MMP inhibitor with a thiol zinc binding group. It has oral bioavailability and is a collagen non-peptide mimetic. Remasistat has some selectivity because it does not inhibit all MMP operations. Remastertat does not inhibit metalloproteases that release, for example, TNF-alpha, TNF-II, L-selectin, IL-1-RII and IL-6. Remmastat is capable of inhibiting MMP1, MMP2, MMP8, MMP9 and MMP 14.

Another example of a broad spectrum MMP inhibitor for use in the methods and apparatus disclosed herein is MMP9 inhibitor I (CTK8G 1150):

in other implementations, the broad-spectrum MMP inhibitors used in the methods and devices disclosed herein inhibit five or fewer, (such as any of 5, 4, 3, or 2 MMPs; or such as 5 or fewer of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP 16). In some embodiments, the broad spectrum MMP inhibitor inhibits at least MMP 9. These more limited broad spectrum MMP inhibitors can be selected based on the particular MMPs expressed in the tissue to be sutured (e.g., inhibiting at least one of MMP8, MMP9, or MMP 13). One example of such a more limited broad spectrum MMP inhibitor suitable for use in the surgical stapler devices disclosed herein is COL-3 (mestasol; CMT-3):

COL-3 IC at 34. mu.g/ml₅₀Inhibition of MMP1 with an IC of 48. mu.g/ml₅₀Inhibition of MMP8, and IC at 0.3 μ g/ml₅₀Inhibits MMP 13.

Another example of a more limited broad-spectrum MMP inhibitor is FN-439:

FN-439 IC with 1 μ M₅₀Inhibition of MMP1, with an IC of 150. mu.M₅₀Inhibition of MMP3 at 1 μ M IC₅₀Inhibition of MMP8, and IC at 30 μ M₅₀Inhibit MMP 9.

Another example of a more limited broad spectrum MMP inhibitor for use in the methods and apparatus disclosed herein is MMP9 inhibitor I (CTK8G 1150):

MMP9 inhibitor I can have an IC of 1.05nM₅₀Inhibition of MMP1 with an IC of 5nM₅₀Inhibition of MMP9, and IC at 113nM₅₀Inhibit MMP 13.

Another more limited range of broad spectrum MMI inhibitors is MMI-166:

MMI-166 is a third generation N-arylsulfonyl-alpha-amino acid glycolate-related MMP inhibitor that selectively inhibits the activity of MMP2, MMP9, and MMP 14.

Simimastat (Ro 32-3555; tokatcet) is another more limited range of N-arylsulfonyl-alpha-amino acid glycolate-related MMP inhibitors that inhibit MMP1, MMP3, and MMP 9:

MMI-270 is another more limited range of broader N-arylsulfonyl- α -zinc aminocarboxylate binding MMP inhibitors that inhibit MMP2, MMP8, and MMP 9:

ABT-770 is another more limited range of N-arylsulfonyl-alpha-zinc aminocarboxylates that inhibit gelatinases (e.g., MMP2 and MMP9) bind to MMP inhibitors:

Promastistat (AG-3340) is a more limited range of broader N-arylsulfonyl- α -zinc aminocarboxylate binding MMP inhibitors with specific selectivities for MMP2, MMP3, MMP9, MMP13 and MMP 14:

among other limitations, MMP inhibitors are based on hydroxy acid esters and inhibit metabolism as well as MMP 1. Examples of such MMP inhibitors are the tetrahydropyran-based MMP inhibitors RS 130830 and 239796-97-5.

Broad-spectrum 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 (Maskos & Bode, 2003). However, in addition to their ability to act as broad-spectrum 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 broad spectrum MMP inhibitor can include a substance that can allow or enhance the MMP inhibitor's adhesion to an exterior surface of a surgical stapler or component thereof, such as an exterior surface of a staple (e.g., a staple leg or staple crown), or an exterior surface of 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 broad spectrum 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 broad spectrum 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 adhesion of broad spectrum MMP inhibitors to the staple region coated with it. For example, the absorbable polymer may be porous to allow liquids containing broad spectrum MMP inhibitors to concentrate and aggregate within the pores in which the MMP inhibitor is retained as the liquid dries. Additionally, one or both of the broad spectrum 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 a broad spectrum of MMP inhibitors as side chain elements to the polymer chain itself. Finally, the water solubility of the polymer itself can be manipulated to allow the polymer and broad spectrum MMP inhibitor to be co-mixed before removing water from the construct while retaining the drug and blended polymer.

In at least some implementations, absorbable lubricants can be used to allow or enhance adhesion of the broad spectrum MMP inhibitor 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 outer surface of an 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, e.g., reservoirs capable of releasably retaining one or more pharmaceutical agents (e.g., at least one broad spectrum 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 injection molded thermoplastic materials or vacuum thermoformed materials. An example of various molded appendages is further described in U.S. patent publication 2013/0221065 entitled "fast card Comprising areleable Attached Tissue Thickness company" 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, needled 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 build 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 Implant And inserted device And Method For Using The Same" filed on 12.9.2007, which are hereby incorporated by reference in their entirety.

The adjunct can 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 broad spectrum 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 factor, Nutropin, Humatrope, Genotropin, Norditropin, Saizen, Omnitrope and biosynthetic growth factors), Epidermal Growth Factor (EGF) (e.g., inhibitors, gefitinib, erlotinib, afatinib and cetuximab), heparin-binding EGF-like growth factors (e.g., epidermal regulators, cytokines, amphiregulin and Epigen), transforming growth factor alpha (TGF-a), neuregulin 1-4, Fibroblast Growth Factor (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 repair-and/or synthesis-inhibiting DNA (e.g., carboplatin, cisplatin, oxaliplatin, and lenacil), retinoids (e.g., tretinoin, alitretinoids, and bexarotene), vinca biological agents that inhibit mitotic base and microtubule formation (e.g., vinblastine, vincristine), vincristine, vinblastine, and microtubule, 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 pharmaceutical agent from the 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 modulate 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 immediately after surgical stapling of tissue by 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 may 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 materials include a releasably effective amount of at least one broad-spectrum MMP inhibitor. As used herein, the term "effective amount" with respect to a broad spectrum MMP inhibitor released according to the devices and methods herein refers to an amount of the broad spectrum MMP inhibitor sufficient to inhibit at least two MMPs to an extent such that tissue strength is increased within the immediate 1-3 days following tissue suturing. Release of a broad spectrum MMP inhibitor in tissue at the site of the suture prevents MMP-mediated extracellular matrix degeneration during healing of the wound in the tissue in a predetermined manner.

In some implementations, the broad spectrum MMP inhibitor is configured to be released from the staple and/or adjunct material and into surrounding tissue two to three days after staple insertion. For example, a broad spectrum MMP inhibitor can be encapsulated in a resorbable polymer (such as any of the resorbable polymers disclosed herein) that begins to break down and release its contents about 48 hours after insertion of the staples into tissue, and lasts 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).

Releasing a sufficient amount of a broad spectrum MMP inhibitor from the plurality of staples and/or adjunct material to inhibit at least five percent (such as any of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% inhibition of proteolytic activity) of the proteolytic activity of the MMP inhibitor(s) expressed at the tissue stapling site immediately upon staple insertion (such as those MMP inhibitors expressed within 1-3 days after tissue stapling, e.g., MMP8 and/or MMP 9). In some embodiments, upon insertion of the staples into the tissue, a sufficient amount of the broad spectrum MMP inhibitor is released from the plurality of staples and/or adjunct material to ensure a concentration of the broad spectrum 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, 1nM 6nM, 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. mu.M, 15. mu.M, 20. mu.M, 25. mu.M, 70. mu.M, 75. mu.M, 80. mu.M, 85nM, 1nM, 23nM, 24nM, 20nM, 60nM, 50nM, 60nM, 50nM, 60nM, 50, 1nM, 5. mu.M, 1. mu.M, 5. mu.M, 1nM, 5. mu.M, 5, 1nM, 5. mu.M, 1nM, 1, 5. mu.M, 5 mu.M, 1, 5M, 5. mu.M, 1nM, 1, 5. mu.M, 1, 5, 1, 5, 1, 5, 1, 25, 20, 5, 1, 20, 5, 20, 1, 20, 1, 5, 20, 1, 25, 1, 20, 1, 20, 25, 1, 25, 1, 5, 25, 1, 25, A broad spectrum MMP inhibitor in a wound site of 90 μ Μ, 95 μ Μ, 100 μ Μ, 125 μ Μ, 150 μ Μ, 175 μ Μ, 200 μ Μ, 225 μ Μ, 250 μ Μ, 275 μ Μ, 300 μ Μ, 325 μ Μ, 350 μ Μ, 375 μ Μ, 400 μ Μ, 425 μ Μ, 450 μ Μ, 475 μ Μ or 500 μ Μ or more, including values falling between these values.

In further implementations, releasing broad spectrum MMP inhibitors from multiple staples and/or adjunct materials 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 broad spectrum 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 broad spectrum MMP inhibitor.

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 15/621,551 entitled "Surgical Stapler with End Effector Coating," U.S. application 15/621,565 entitled "Surgical Fastener Device for the prediction of ECM Degradation," and U.S. application 15/621,572 entitled "Surgical Stapler with Controlled conditioning," which are filed on even date herewith and incorporated by reference herein in their entirety.

Those skilled in the art will recognize additional features and advantages of the present invention based on 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 (2)

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

an effective amount of at least one broad spectrum Matrix Metalloproteinase (MMP) inhibitor effective to prevent MMP-mediated degeneration of the extracellular matrix during healing of the wound in a predetermined manner in the tissue, wherein the at least one broad spectrum MMP inhibitor is disposed on at least a portion of the plurality of staples; and is

Wherein the MMP inhibitor inhibits four or less of MMP1, MMP2, MMP3, MMP9, MMP12, MMP13, MMP14, and MMP16, and wherein the MMP inhibitor is one or more inhibitors selected from the group consisting of MMI-166, tanostat, cerostat, MMI-270, ABT-770; and is provided with

Wherein the MMP inhibitor comprises an absorbable polymer configured to allow for promoting adhesion of the MMP inhibitor to an outer surface of the staple, wherein the absorbable polymer and the MMP inhibitor are configured with ionic charges, thereby allowing for their electrostatic attraction.

2. The staple cartridge assembly of claim 1, further comprising a biocompatible adjunct material releasably retained on said cartridge body and configured to be deliverable to tissue by deployment of said staples in said cartridge body, wherein said MMP inhibitor is encapsulated on said adjunct material by an absorbable polymer or attached as a side chain molecule thereon.

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