BRPI0706906A2 - tissue-adherent multilamellar sheet, method of manufacturing a sheet, a device suitable for implantation in the human or animal body and method of attaching a tissue surface to another tissue, or sealing a tissue surface - Google Patents

Abstract

MULTILAMELLAR SHEET ADHESIVE TO FABRIC, METHOD OF MANUFACTURING A SHEET, APPROPRIATE DEVICE FOR IMPLANTING IN THE HUMAN OR ANIMAL BODY AND TJNIAO METHOD OF A TISSUE SURFACE TO ANOTHER FABRIC OR SEPARATING A SURFACE WOVEN. multilamellar sheet adhering to a fabric comprising a layer or structural laminate attached to a contact layer with the fabric. The structural layer or laminate comprises one or more synthetic polymers that have film forming properties and the layer of material in contact with the fabric contains tissue reactive groups. Synthetic polymers that have film forming properties are preferably biodegradable polyesters, and tissue reactive groups are more preferably NHS ester groups.

Description

FABRIC ADHESIVE MULTI-FAMILY SHEET, ONE-SHEET DEMANUFACTURE METHOD, APPROPRIATE FOR HUMAN OR ANIMAL BODY IMPLANTS, AND THE FABRIC FOR UNIONING A FABRIC OR OTHER FABRIC SIDE SURFACE

FIELD OF INVENTION

The present invention relates to a flexible sheet suitable for use as an adhesive and a sealant which lends itself to topical application to the internal and external surfaces of the body for therapeutic purposes.

The invention also relates to a process for preparing such a sheet and the methods of using such a sheet. In particular, the invention relates to a self-adhesive, biocompatible and hydratable polymeric sheet which may be used for therapeutic purposes such as deferred healing, binding, sealing and strengthening of weakened tissue and for the application of therapeutic agents and for a preparation process. and methods of using such a sheet. The invention further relates to implantable medical devices coated with sheet-like material.

BACKGROUND OF THE INVENTION

There is considerable interest in the use, for a variety of surgical or other therapeutic applications, of materials that adhere to biological tissues, for example as an alternative to the use of mechanical fasteners such as sutures, staples, etc. Material formulations which have been proposed so far include swabs or viscous gels that are manufactured in this way or are prepared immediately prior to use by mixing the ingredients. Such formulations are then applied to the tissue surface using a suitable applicator device such as a syringe.

Formulations of the type described above suffer from a number of disadvantages. If the formulation has a low viscosity, it may spread over the application area and thereby make it difficult to accurately apply to the desired detained area. If the formulation is more viscous on the other hand, it may be difficult to distribute. In either case, the formulation, being prepared in hydrated form, may have a limited life and may be subject to premature cure. It may therefore be necessary for the whole of the formulation to be used at once or to be discarded. In addition, preparation of formulations immediately prior to use by mixing the ingredients is obviously labor-intensive and may require the use of additional apparatus. In addition to these drawbacks, the degree of adhesion between tissue surfaces that is provided by such formulations may be less than wanted.

Tissue-adherent material formulations have also been applied to supports suitable for application to the tissue surface. The use of therapeutic materials in the form of a sheet, patch or film for topical administration to the internal or external organs of the body is well documented for a wide range of medical applications. A disadvantage of the proposed products so far, however, is that the degree of adhesion to the underlying fabric beyond their cohesive strength, particularly for a longer term, may be inadequate. Although initial adherence may be satisfactory, the leaf may subsequently detach gifted, often after only a few seconds or minutes, for example as a result of leaf hydration after application. In addition, the flexibility of the product may be insufficient to conform easily to the surface to which it is applied, which may also have an adverse effect on its adherence. As a result of improper adherence of these products, it may be necessary to provide additional reinforcement, for example, through mechanical fixation when using sutures, staples, or still others. Alternatively, energy (e.g., heat or light energy) may be applied in order to initiate chemical bonding of the adherent formulation to the underlying tissue and thereby initiate the bonding of tissue surfaces to each other. Clearly, such approaches introduce additional drawbacks. The use of mechanical fixations such as sutures or staples is often in fact the purpose for which the use of such products is intended to replace or prevent. In many cases, the use of such fixations is not completely effective (for example, in the lungs) or undesirable, as their introduction results in other areas of tissue weakening. The use of external energy requires the provision and operation of a source of such energy. Such energy sources can be expensive and difficult to operate, particularly within the confines of an operating room or similar environment. In addition, the use of external energy for fixation can be time consuming and (in some cases) requires significant careful judgment by the surgeon to assess when sufficient energy has been applied to fix without damaging the underlying tissue.

A disadvantage of wing-type products such as described above is that they may not have the degree of flexibility that may be necessary or desirable for many applications. This is particularly true for products used in the increasingly important field of endoscopic surgery (keyhole), which may require the product to be folded or rolled into a compact configuration prior to introduction into the body. Attempts to make such products more flexible, for example through the inclusion of plasticizers, may have the effect of reducing the product's ability to adhere.

Improvements have been devised for the fabric-like or other sheets of the general type described above and related applications of adherent material, which substantially outweigh or attenuate the above and / or other prior art disadvantages.

BRIEF DESCRIPTION OF THE INVENTION

According to a first aspect of the invention, there is provided a multilamellar fabric-adhering sheet comprising a structural layer or laminate, whose structural layer or laminate comprises one or more polymersynthetics having film-forming properties and to which the structural layer or laminate is bonded to a layer of tissue contact material containing tissue reactive groups.

The sheet according to the invention is advantageous mainly because it binds effectively to the fabric, allowing it to be used in a variety of medical applications. It has been found that the sheet offers greater flexibility and yet retains the ability to adhere well. In preferred embodiments, the sheet exhibits good initial adhesion to the tissue to which it is applied (and may thus be described as "self-adhering") and, furthermore, remains well-adhered to the tissue for a longer period of time. Without wishing to be bound by any theory, it is believed that the initial adhesion of the sheet to the tissue is attributable to the electronic bonding of the sheet to the tissue, and is supplemented or replaced by the covalent chemical bond between the tissue-reactive functional groups of the formulation and the tissue, particularly between the two. amine and / or thiol groups on the endowed surface and leaf tissue reactive functional groups.

Initial adhesion of the sheet to the tissue surface is believed to occur due to Van der Waalse forces / or hydrogen bonding between the sheet and the provided surface. On contact with the tissue surface, the sheet becomes hydrated, thereby causing the reaction between the tissue reactive functional groups and the underlying surface provided. Such reactions between the reactive reactive functional groups and the underlying tissue result in a high adhesion between the leaf and the tissue surface. The leaf can absorb physiological fluids (as a result of application to exudative tissue surfaces) and any additional solutions used to hydrate the leaf after application (such fluids may be the solutions commonly used in surgical irrigation), becoming more compatible with and adhering to tissue surfaces. thus, an adherent sealant with hemostatic and pneumostatic functions.

Use of the sheet reduces or eliminates the need for additional mechanical fastening devices (eg sutures or staples) or the need to apply external energy in the form of heat or light to cause the sheet to adhere to the underlying tissue. Another advantage of the sheet according to the invention is that it is applied to the fabric as a preformed article, rather than being prepared by mixing materials immediately prior to use.

In addition, since the leaf is essentially inactive until it is hydrated upon contact and after contact with the tissue surface, the leaf is not prone to premature reaction and as a result its storage life may be considerable, for example. of more than six times properly stored at room temperature.

By the term "sheet" is meant an article with a thickness that is considerably smaller than its other dimensions. Such an article may alternatively be described as a patch or a film.

In preferred embodiments of the invention, the structural layer or laminate is a laminate comprising two or more distinct layers which are joined together. In particularly preferred embodiments, the laminate comprises alternate polymer layers having film forming properties and the material containing reactive functional groups. In general, it has been found that sheets comprising a structural laminate have a better performance in terms of tissue adhesion and / or elasticity and / or maintenance of structural integrity than leaves with a single structural layer.

In such a case, the sheet according to the invention preferably comprises a uniform number of layers and, in particular, alternating film-forming polymer layers and the reactive group-containing material. The sheet may then be considered to comprise a structural laminate comprising η film-forming polymer layers with η-1 layers of recreational material interspersed therewith and a layer of material contacting the tissue reactive fabric. The value of η may be 1, in which case the sheet simply comprises a single structural layer and the contact layer with the fabric.

Alternatively, η may be 2 or 3, in which case the sheet comprises four or six layers in total. Leaves where η = 2 are currently preferred.

Material containing reactive functional groups may be the same or similar to tissue reactive material as the tissue contact layer.

In another aspect of the invention there is provided a suitable device for implantation in the human or animal body, whose device contains at least part of its outer surface a coating comprising one or more polymers with film-forming properties, at least part of said coating being attached to a material layer comprising tissue reactive functional groups.

In this aspect of the invention, the film-forming polymer coating provides a means for securing the device-comprising material comprising tissue-reactive functional groups, the latter material providing a means for anchoring the device to its desired position within the body. This aspect of the invention may therefore be of particular utility with respect to implantable devices which must otherwise be difficult to fix in position within the body, for example because they are made of a material that is chemically inert and unresponsive to tissue reaction. surrounding or with the chemical linking groups.

In the following detailed description of the invention, reference is made primarily to embodiments of the invention which are in the form of sheets. It should be appreciated, however, that analogous comments apply, where appropriate, to embodiments of the invention involving coatings on implantable devices.

In another aspect, the invention also provides a method of attaching a fabric surface to another fabric or sealing a fabric surface, the method comprising applying to the fabric surface a sheet according to the first aspect of the invention.

The sheet according to the invention may also be used for the application of one or more therapeutically active agents or anti-infection agents to the site to which the sheet is applied. In such a case, the agent (s) may be incorporated into the sheet, for example by mixing with the other ingredients which are used in the manufacture of the sheet. Alternatively, the agent (s) may be covalently attached to a leaf component. However, in. In other embodiments, the sheet is free of therapeutically active agents.

Similarly, one or more therapeutically active agents may be incorporated into the material applied to the outer surface of an implantable device according to the second aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

<table> table see original document page 9 </column> </row> <table> poly (VP-AAc-AAc (NHS)) pyrrolidone vinyl terpolymer, acrylic acid and NHS acrylic acid ester

Nature of the structural layer or laminate The sheet according to the first aspect of the invention includes a structural layer or laminate comprising at least one film-forming polymer. The layer or structural laminate may consist wholly or substantially entirely of cell-forming polymer. In other embodiments, the structural layer or laminate consists primarily of the film-forming polymer. For example, the structural layer or laminate may comprise more than 80%, more than 90% or more than 95% weight / weight of film-forming polymer.

A variety of suitable film-forming polymers may be used for first layer formation, as long as they exhibit appropriate film-forming properties in conjunction with suitability for medical applications, in particular the absence of toxicity, biocompatibility, and usually biodegradability.

Most commonly7 the first layer comprises only one film-forming polymer. Alternatively, the first layer may be formed of more than one film polymer.

The film-forming polymer may be synthetic or may be derived from a natural material.

A particularly preferred group of polymersynthetics that may be suitable for use in the invention includes biodegradable polyesters. Specific examples of such polymers include polylactic acid and polyglycolic acid, and copolymers and mixtures thereof. Other examples include polycaprolactones and polyhydroxyalkanoates, such as polyhydroxy butyrate, polyhydroxyvalerate and polyhydroxy hexanoate. Currently preferred polyester polymers for use in the invention are depoly (lactide-co-glycolide) copolymers [also referred to as poly (lactic-co-glycolic) acid], which are generally biodegradable and biocompatible, and are soluble in a broad range of organic solvents.

In presently preferred embodiments of the sheet, which comprise a structural laminate, particularly preferred embodiments are those comprising alternate layers of biodegradable polyester material and material containing reactive functional groups. Thus, in a specific aspect of the invention there is provided a multilamellar fabric-adhering sheet comprising a structural laminate, the laminate comprising layers of a n-1 layer biodegradable polyester containing the interleaved reactive functional groups and a contact layer. with the tissue of the tissue reactive material, where η has a value of 1, 2 or 3, most preferably 2.

In such embodiments, the distal layer to the fabric-contact layer is polyester, which is substantially non-adherent to the fabric. Such leaves will generally adhere, therefore, only to the target tissue (to which the tissue contact layer containing tissue reactive functional groups is applied) and not to the surrounding tissues (e.g., pleural or peritoneal appearance).

Other examples of synthetic polymers that may be suitable include amino polymers such as PEGsaminates (including those marketed under the trade name JEFFAMINE) and polyallylamines.

In addition, the film-forming polymers that may be suitable for use in the invention are polysaccharides and, in particular, the basic polysaccharides. Nature of the tissue contact layer The sheet according to the first aspect of the invention has a contact layer with tissue comprising a material that contains tissue reactive functional groups. Such material preferably comprises one or more polymers containing tissue reactive functional groups.

By "tissue-reactive functional groups" is meant functional groups capable of reacting with other functional groups present on the surface of the tissue to form covalent bonds with the tissue. Tissues generally consist partially of proteins, which generally contain thiol and portions of primary amine. Many functional groups such as imido ester, p-nitrophenyl carbonate, NHS ester, epoxide, isocyanate, acrylate, vinyl sulfone, orthopyridyl bisulfide, maleimide, aldehyde, iodoacetamide and others may react with thiols or primary amines and therefore "reactive functional groups craving". As used herein, the terms NHS or NHS ester lend themselves not only to their own N-hydroxy succinimide, but also derivatives thereof where the succinimidyl ring is substituted. A detailed example derived is N-hydroxy sulfosuccinimidyl and damesma salts, particularly sodium salt, which may increase the solubility of the tissue reactive material.

Tissue-reactive functional groups that may be useful in the present invention include any reactive functional groups (under the prevailing conditions when the formulation is applied to the tissue, i.e. in an aqueous environment and without the application of significant amounts of heat or other energy). external) with the functional groups present on the tissue surface. The latter class of the functional group includes thiol and amine groups, and tissue reactive functional groups therefore include thiol and / or amine groups. Examples include: imido ester; p-nitrophenyl carbonate NHS ester; epoxide; isocyanate; acrylate; vinyl sulfone; orthopyridyl bisulfide; maleimide; NHS aldehyde and iodoacetamide. NHS ester is a particularly preferred preferred reactive acid group.

In addition to tissue-reactive functional groups, the polymer (s) constituting the material of the second layer may contain functional groups which, while not themselves reactive to the tissue to which the sheet is applied, impart Good contact adhesion between the sheet and fabric. Such functional groups are referred to in the present invention as "nonreactive functional groups". Examples of non-reactive functional groups include hydroxyl, asamines or heterocyclic amides (e.g., vinyl pyrrolidone residues) and particularly carboxyl groups (e.g. acrylic acid residues).

It is particularly preferable that tissue reactive functional groups be activated derivatives of nonreactive functional groups. In certain embodiments, all nonreactive functional groups may be activated to form tissue reactive functional groups. In other embodiments, only some of the nonreactive functional groups can be activated to form tissue reactive functional groups. In the latter case, the initial stickiness resistance of the leaf contact to the tissue to which it is applied and the longer-term bond strength caused by the covalent reaction of the tissue-reactive functional groups with the functional groups in the tissue may be varied and controlled by varying the proportion of the leaves. nonreactive groups that are in activated form.

NHS ester is a particularly preferred preferred reactive reactive functional group, and therefore the preferred tissue reactive polymers are ester rich NHS polymers. Particularly preferred tissue reactive polymers are poly (VP-AAc (NHS)) and poly (VP-AAc-AAc (NHS)) terpolymer.

The sufficiency of the initial degree of adhesion of a sheet to the tissue by the bioadhesive polymer (s) can be quantitatively determined in vitro, for example by performing an adhesion strength test. This test is performed by allowing the sheet to be adhered to an appropriate substrate (placed in a fixed position), while the sheet itself is physically attached at a separate point to the load of a stress tester, positioned so that, prior to testing, the sheet not under load. The load cell is movable along an axis substantially perpendicular to that along which the substrate is positioned. The test involves the movement of the load cell away from the substrate at a constant predetermined rate until it detaches from the substrate. The test output is a quantitative measure of the bonding energy for that sheet - that is, the cumulative amount of energy required to break the interaction between the sheet and the substrate to which it is adhered. An appropriate cumulative adhesion energy for the sheet according to the invention should be no less than 0.5 mJ.

In certain embodiments of the invention, a preferred tissue reactive polymer is depoly terpolymer (VP-AAc-AAc (NHS)). Poly (VP-AAc) carboxyl groups can be converted to NHS esters by reaction with NHS in the presence of DCC (see Example 9). If the dopoli acid content (VP-AAc) is determined (in moles), the proportion of acidic groups converted to tissue reactive groups can be controlled by adding the desired percentage of NHS in moles.

Another usable tissue-reactive polymer which contains hydroxyl groups is an activated form of HPC succinate, for example NHS succinate from PCH. In this case, some of the hydroxyl groups are activated with NHS via succinic acid binding (see Example 11).

The properties of the fabric adherent sheet can be optimized by including other additive polymers.

Property Enhancing Additives

Although generally the sheet according to the first aspect of the invention has adequate flexibility, it may nevertheless be desirable to further increase the flexibility, elasticity and / or wet strength of the sheet by the addition of one or more plasticizers and elastomers to the layer. or the structural laminate and / or tissue contact layer. In particular, low molecular weight species such as glycerol and low molecular weight PEG may be incorporated into the formulations to increase flexibility. Examples of suitable elastomers that may be incorporated into the product include poly (caprolactones), ospoli (urethanes) and the poly (silicones).

Such materials may increase the flexibility and / or elasticity of the sheet when added at levels of up to 30% by weight of the ingredients constituting the sheet.

However, the inclusion of high levels of such materials may have a detrimental effect on adherent leaf performance. To rule out this disadvantage, additives may be used to include the reactive functional groups that may participate in tissue adhesion.

Earplugs

Reaction between leaf tissue reactive functional groups and tissue surface functional groups could vary with pH. It may therefore be preferable to protect the surface of the fabric just prior to application or, more preferably, to include a buffer in the formulation used to prepare the sheet, in particular the tissue contact layer of the sheet. The average stickiness of certain sheets according to the invention for explanted liver can be increased by buffering the tissue surface with phosphate / carbonate buffer at pH10.5.

Bonding of sheet components during manufacture

The layer or structural laminate materials and / or the fabric contact layer may be joined during the manufacturing process. Such joining may increase the physical strength of the sheet and may optimize the properties of the sheet, in particular in terms of the time required for sheet biodegradation after it has been applied.

Bonding can be caused by a variety of devices, including the shaping of common solvent component layers. A further method involves a formulation from which the structural layer or the laminate and / or the tissue contact layer are prepared which comprises at least two functional groups which may react with the functional groups present in the material to be joined. This component will therefore act as a crosslinking agent.

Preferably, the crosslinking agent contains at least two functional groups in the same manner. Thus, the crosslinking agent is most preferably a homobifunctional or homopolifunctional crosslinking agent.

Physical form of the leaf

The sheet may typically have a total thickness of 0.01 to 1 mm, typically 0.01 to 0.5 mm, and more generally 0.015 to 0.2 mm or 0.015 to 0.1 mm, for example 0.015a. 0.05 mm. In presently preferred embodiments, the thickened tissue contact layer is larger than the thickened layer or structural laminate. For example, the fabric-contact layer may have a thickness explaining more than 50% of the total sheet thickness, or more than 60%.

The sheet may be produced with, or subsequently cut to, dimensions of a few square millimeters to several tens of square centimeters.

Sheet manufacture

More conveniently, the sheet according to the invention may be prepared by the step formation of the individual layers constituting the sheet.

The structural layer or (as preferred) the structural laminate layer which is distal to the fabric contact layer may be prepared first, for example by shaping a solution of the material constituting that layer in a suitable solvent, in a suitable plate or mold or on a suitable release paper, for example, a silicone coated release paper. The pouring solution is then dried or allowed to dry, optionally under conditions of elevated temperature and / or reduced depression.

Successive layers of the structural laminate may then be poured over the first preformed layer, followed in each case by drying to remove the solvent, and appropriate curing to achieve a desired degree of crosslinking. Acura is most preferably promoted by applying high temperatures (typically up to one hour or more at temperatures up to 600 ° C or higher).

Finally, the fabric contact layer may be molded into the structural layer or laminate. Again, this is preferably followed by drying to remove solvent and curing to a desired degree of crosslinking. Curing preferably takes place at least partially at elevated temperatures (typically within ten minutes and up to one hour or more at temperatures up to 60 ° C).

Each sheet layer can be poured in a single operation. Alternatively, particularly for layers which are relatively thick (i.e., which are thick relative to other layers of the sheet), a layer may be composed by successive casting of finer sublayers.

Once manufactured, and prior to use, the cork according to the invention will typically have a water content of less than 10 wt% and more generally less than 5 wt%.

During manufacture, an alphanumeric image or indication may be printed on the surface of the individual layers of the sheet. This indication may be used to distinguish the tissue-adherent surface from the non-tissue-adherent surface. Alternatively, it may be used to denote the identity of the product or manufacturer. A chromophore that can be used as a labeling agent includes methylene blue.

Typically, implantable devices according to the invention may be prepared by any convenient method of applying the coating device. For example, the coating layers may be molded into the device in a manner analogous to the manner in which the structural layer or laminate materials and the fabric contact layer are molded as described above. Alternatively, the coating may be applied by dipping a device into liquid formulations or by spraying the device with liquid formulations.

Therapeutic Applications of the Sheet The sheet according to the invention is suitable for application to internal and external surfaces of the body, i.e. it can be applied topically to the external part of the body (for example to the skin) or to internal surfaces such as organ surfaces. exposed during surgical procedures, including conventional and minimally invasive surgery.

The foil according to the invention is particularly suitable for surgical applications in the following areas:

Thoracic / cardiovascularGeneral surgeryONG

Urology

Oral / maxillofacial OrthopedicNeurologicalGastroenterologyOphthalmologyGynecology / obstetrics

Possible uses are described in more detail below.

Wound healing

The degradable nature of the leaf means that it can support and promote wound healing during internal and topical procedures. Once the leaf begins to degrade, the fibroblasts will move and begin to adhere to extracellular matrix components. The sheet can therefore be used as an internal or external dressing. In addition, factors such as ecAMP growth factors, which are known to promote epithelial cell proliferation, can be added to the para-auxiliary formulation in the healing process. The sheet can be designed to control the transmission of moisture and infectious agents, and is therefore particularly useful for burn treatment.

Skin ClosureThe leaf may be applied topically to promote wound closure (as an alternative to sutures). This may have beneficial effects, including scar reduction, and the formulation and leaf may also be useful for aesthetic purposes during major surgery (eg in Accident & Emergency Departments). The self-adhering properties of the sheet can make it easy to apply quickly.

Hernia repair

The leaf may be used to provide reinforcement in hernia repair procedures. Self-clamping fixation overcomes the potential problems faced by conventional surgical reinforcement products that require suturing or stapling in an already weakened area. The foil for such a procedure may be designed to be short or long lasting, depending on the degree of repair of the tissue required. The sheet can also support the application of graphs.

The invention may also find application in the provision of a coating adhering to hernia roofing devices.

Anastomosis

The foil provides a means for rapid sealing and prevention of leaks from joined tubular structures, such as blood vessels and vascular and bladder grafts, and gastrointestinal tract. The ability of the sheet to withstand tissue repair can be of particular value if used in nerve repair.

Sealing large areas of fabric

Good sealing and leaf handling properties, combined with its properties and self-adhering ability to cover a large surface area, mean that it can be of particular use for sealing of dry tissue surfaces - in particular those where diffuse bleeding is a problem. problem (for example, the liver). The sheet also provides an ideal support matrix for tissue repair in such locations. This could also be applicable to limit cerebrospinal fluid leakage following neurological surgery.

Air leak seal

In addition to the plaster properties described above, the high tensile strength and good inherent elasticity of the sheet (upon hydration and reaction of the reactive functional groups to tissue) make it particularly suitable for preventing air leakage in the lung, particularly after lung resection. Again, after sealing, the cork provides an ideal support matrix for repair provided at such locations.

Haemostasis

The foil can be applied to a bleed area, acting as a physical barrier. Leaf tissue-reactive material can immobilize proteins and thereby promote hemostasis.

Administration of therapeutic agent

Drugs, anti-infection agents and other therapeutic agents (including biologically active agents such as growth factors and even cells and cell components) may be added to the solution (s) used to form leaf components, or may be linked together. covalently to components prior to their use in sheet manufacture. Since the leaf is in place, upon application to the desired site, the drug will be released slowly by diffusing or projecting the leaf, for example by controlling the degree of crosslinking within it, so that as it degrades with Over time, the drug is released. The release rate can be controlled by the appropriate sheet design. The leaf may thus provide a means for applying a known amount of drug systemically or to a precise locus. The drug may be directly attached to a solution component used in the manufacture of the sheet or simply dispersed in the solution.

Prevention of postoperative adhesions

Postoperative adherence, the formation of unwanted connective tissue between adjacent tissues, is a serious problem that can cause major postoperative complications. It is a particular problem in intestinal surgery where it may cause, for example, intestinal torsion, which may then require surgical intervention. additional. Application of the sheet material according to the invention to tissues exposed in a surgical procedure may be effective in preventing postoperative adhesions between such surrounding tissues and tissues.

Minimally Invasive Procedures

The use of minimally invasive techniques for biopsy tissue sampling, device introduction, application of therapeutic agents, and surgical procedures is rapidly developing as a good alternative to traditional "open" surgery. Minimally invasive procedures typically result in less pain and scarring, faster recovery, and fewer postoperative complications for patients, as well as a reduction in health care costs. Procedures are undertaken by using specially designed instruments that are inserted through small surgical incisions of the size of a keyhole. The sheet may be introduced into the body through existing, specially designed minimally invasive surgical instruments and trocar systems, and the sheet may be formed or prepared to an appropriate size and configuration, including struts for use with stapling devices. The flexibility of the sheet allows it to be formed into a small size configuration, for example by folding or curling the sheet, and thereby facilitates the use of the sheet in minimally invasive surgical procedures and / or other procedures where access is restricted. Good adhesion of initial contact of the sheet to the tissue to which it is applied may also be particularly useful in such procedures.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 shows schematically and without scale the structure of an embodiment of a fabric-adhering sheet according to the invention.

Figure 2 illustrates the synthesis of poly (N-vinylpyrrolidone50-co-acrylic acid25-co-acrylic acid-N-hydroxysuccinimide ester25)

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will now be described in greater detail, by way of illustration only, with reference to the following examples. Examples 1 and 2 describe the manufacture of fabric-adherent sheets according to the invention. Examples 3 to 5 describe the performance and characteristics of such sheets. Examples 6 and 7 describe the synthesis of material containing tissue reactive groups that is used in the sheets of Examples 1 and 2. Example 8 describes the synthesis of an alternative form of material. tissue reactive.

EXAMPLE 1

PREPARATION OF THE MULTI-YELLOW SHEET A multilamellar sheet adhering to the fabric according to the invention is shown schematically in Figure 1. The sheet comprises a structural laminate and a tissue contact layer.

The structural laminate has the form of:

a) a first layer 1 of PLGA;

b) a second poly (VP-AAc-AAc (NHS)) layer 2; and

c) a third layer 3 of PLGA.

The tissue contact layer 4 is joined to the third layer 3 and comprises poly (VP-AAc-AAc (NHS)).

Each of the first and third layers 1 and 3 has a thickness of approximately 4 μτη, and the second layer 2 has a thickness of approximately 3 μτη. Tissue contact 4 has a thickness of approximately 22 μτη and consists of three sublayers 4a-c with approximately equal thicknesses.

The sheet is prepared as follows:

1.1 Preparation of Solutions

Three solutions are prepared as follows:

Solution A consists of 10 g PLG dissolved in 100 ml DCM.

Solution B consists of 7.5 g of poly (VP-AAc-AAc (NHS)) dissolved in 100 ml DCM / MeOH 15/4.

Solution C consists of 2.5 g of methylene blue dissolved in 50 ml of water.

1.2 Layer 1 Leakage

Solution A is poured onto release paper coated with silicone using a device indicated as a bar barra. The film is dried by trinminutes at 20 ° C / atmospheric pressure. The film is not removed peeling paper.

1.3 Layer 2 Leakage

Solution B is poured over Layer 1 when using a bar Κ. The film is dried for thirty minutes at 20 ° C / atmospheric pressure. The film is not removed from the peel paper.

1.4 Logo Application

Solution C is printed on the surface of Layer 2 to form a visualization / logo.

1.5 Layer 3 Leakage

Solution A is poured over Layer 2 by using a bar Κ. The film is dried for thirty minutes at 20 ° C / atmospheric pressure. The film is not removed from the peel paper.

1.6 Layer 4a to c Leakage

Solution B is poured over Layer 3 by using a bar Κ. The film is dried for thirty minutes at 20 ° C / atmospheric pressure. The film is not removed from the peel paper.

Solution B is poured over layer 4a by using a bar Κ. The film is dried for thirty minutes at 20 ° C / atmospheric pressure. The film is not removed from the peel paper.

Solution B is poured over layer 4b by using a bar Κ. The film is dried for sixteen hours at 20 ° C / reduced pressure. The film is not removed from the peeling paper.

1.7 Court

The product is cut to size using specially designed cutters and is detached from the self-supporting paper.

1.8 Final drying

The product is dried for 24 hours at 20 ° C / reduced pressure.

EXAMPLE 2

ALTERNATIVE PREPARATION OF THE MULTI-YELLOW SHEET A two-layer fabric adhering sheet according to the invention comprises a structural layer and a tissue contact layer.

The structural layer is in the form of a single first layer of PLGA.

The tissue contact layer 2 is joined to the first layer 1 and comprises poly (VP-AAc-AAc (NHS)).

The first layer 1 has a thickness of approximately 15 μιι. The tissue contact layer 2 has a thickness of approximately 22 μπι.

The sheet is prepared as follows:

2.1 Preparation of Solutions

Three solutions are prepared as follows:

Solution A consists of 10 g PLG dissolved in 100 ml DCM.

Solution B consists of 10 g of poly (VP-AAc-AAc (NHS) dissolved in 100 ml DCM / MeOH 15/4.

Solution C consists of 2.5 g of methylene blue dissolved in 50 ml of water.

2.2 Layer 1 Leakage

Solution A is poured onto release paper coated with silicone using a device indicated as a bar barra. The film is dried by trinminutes at 20 ° C / atmospheric pressure. The film is not removed peeling paper.

2.3 Layer 2 Leakage

Solution B is poured over layer 1 when using a bar Κ. The film is dried for thirty minutes at 20 ° C / atmospheric pressure. The film is not removed from the peel paper.

2.4 Logo Application

Solution C is printed on the surface of Layer 2 to form a visualization / logo.

The product is cut to size using specially designed cutters and is detached from the self-supporting paper.

2.6 Final Drying

The product is dried for 24 hours at 20 ° C / reduced pressure.

EXAMPLE 3

IN VITRO ADHERENT PERFORMANCE

The in vitro adherent liver performance of a leaf according to the invention was quantified by using a Zwick universal testing machine. After a five minute immersion in DPBS, the average sticking capacity is typically 7 to 14 mJ.

EXAMPLE 4

PHYSICAL CHARACTERISTICS

The product is a transparent / opaque film with a visible logo around it. Tensile strength is typically as high as 2 to 9 Mpa when using a Zwick universal testing machine.

EXAMPLE 5

ADHESIVE PERFORMANCE IN VIVO

The sheets of the type set forth in Example 1 were used to eliminate blood, fluid and air leakage from standard perforation biopsy lesions to the lung and liver tissue.

After application, the foil adheres firmly to the tissue surface and results in immediate dolocal stabilization of the lesion, resulting in satisfactory haemostasis and / or pneumostasis.

Healing evaluated macroscopically and by histological examination of the tissues fourteen days after application reveals good healing and sealing of the original lesion site with normal tissue adjacent to the rest of the leaf. Ostensados remain encapsulated by a fibrous coating. The remaining material continues to be reabsorbed by macrophage activity and cellular infiltration, which is nearly complete in fifty days.

EXAMPLE 6

POLY TERPOLYMER SYNTHESIS (VP-AAC-AAC (NHS))

The reaction is shown schematically in Figure 2.2.000 ml of deoxygenated DMSO is heated to 80 ° C. 121.3 g (1.09 mol) NVP and 78.7 g (1.09 mol) AAA are added to the DMSO, followed by 0.04 g (2.44 χ 10 4 mol) AIBN. maintained at 80 ° C for seventeen to 17 hours and is then placed to cool to room temperature 125.6 g (1.09 mol) of NHS is dissolved in the polymer solution, followed by the addition of 112.6 g (0.545 mol) of DCC. dissolved in 225 ml DMF Sandation is stirred at room temperature for 96 hours The reaction by-product, DCU, is filtered off under reduced pressure using a sintered glass filter The polymer is isolated by mixing with 2,000 ml IPA followed by precipitation of 13,000 ml diethyl ether followed by filtration The polymer is washed three times in 2,500 ml diethyl ether and then dried at 40 ° C under reduced pressure.

The polymer is further purified to remove insignificant amounts of contaminants by Soxhlet extraction using IPA.

The Soxhlet extracted polymer is further purified by preparing a 6% by weight / volume solution in DCM / MeOH (15/4 volume / volume) and then precipitation from a fifty-fold excess of diethyl ether followed by subsequent washing in diethyl ether. . The polymerized polymer is dried at 40 ° C under reduced pressure. Approximate molecular weights Mn = 2-5,000, Mw = 10-30,000.

EXAMPLE 7

ALTERNATIVE SYNTHESIS OF POLY TERPOLYMER (VP-AAC-AAC (NHS))

400 ml of deoxygenated toluene is heated to 80 ° C. 31.6 g (0.28 mol) NVP and 20.6 g (0.28 mol) AAc are added to toluene followed immediately by 0.1 g (6.1 x 10 4 mol) AIBN. The reaction is maintained. at 80 ° C for seventeen and nineteen hours The polymer is isolated by precipitation in 2000 ml of 1/1 volume / volume of hexane / diethyl ether followed by filtration under reduced pressure The polymer is washed three times with 300 ml of diethyl ether and finally dried under vacuum at 40 ° C.

The acid content of the poly (VP-AAc) copolymer is determined by titration against 1.0 M sodium hydroxide. 50 mol% of the acid groups are converted to NHS ester by reaction with NHS in the presence of DCC. 33.7 g depoli (VP-AAc) containing 0.77 mol of acrylic acid functionalities and 44.54 g (0.38 mol) of NHS are dissolved in 1000 ml DMF at 25 ° C. 79.77 g (0.38 mol) of DCC is dissolved in 137 ml of DMF and added to the polymer solution, and the sand is stirred at 250 ° C for 96 hours. The reaction by-product, DCU, is removed by filtration under reduced pressure using a synthesized glass filter. The polymer is isolated by the addition of 1,250 ml of IPA, followed by precipitation of 5,000 ml of diethyl ether, followed by filtration. The polymer is washed three times in 1,000 ml of ethyl ether and is then dried at 400 ° C under reduced pressure.

The polymer may be further purified to remove insignificant amounts of contaminants by a variety of generally known methods, for example, Soxhlet extraction, dialysis or autilization washing of an appropriate solvent such as IPA. In addition, drying at elevated temperature under reduced pressure can remove insignificant amounts of solvents and other volatile materials.

The polymer is further purified to remove insignificant amounts of contaminants by Soxhlet extraction using IPA.

The Soxhlet extracted polymer is further purified by preparing a 6% by weight / volume solution in DCM / MeOH (15/4 volume / volume) and then precipitating a 50-fold excess of diethyl ether, followed by subsequent washing in diethyl ether. The purified polymer is dried at 40 ° C under reduced pressure.

EXAMPLE 8

NHS SYNTHESIS HPC SUCCINATE

10 g HPC (approximately 370,000 Mw) is dissolved in 350 ml anhydrous N-methyl pyrrolidone at 80 ° C.1.4 g (0.014 mol) succinic anhydride and 1.71 g (0.014 mol) 4-dimethyl amino pyridine are added. The reaction is maintained until the next morning at 80 ° C. The solution is cooled to room temperature and 400 ml of IPA is added. Opolymer is precipitated from 3,000 ml of diethyl ether, and is filtered and washed successively with 300 ml of diethyl ether. Finally, the polymer is dried under vacuum at 40 ° C.

The polymer is then dissolved in DMF and reacted with NHS in the presence of DCC to form the thiol and amine NHS-reactive ester compound.

Claims (29)

1. FABRIC ADHESIVE MULTILAMELAR SHEET, characterized in that it comprises a structural layer or laminate, whose structural layer or laminate comprises one or more synthetic polymers having film-forming properties and whose structural layer or laminate is joined to a layer of fabric-contacting material. which contains tissue reactive groups. Sheet according to claim 1, characterized in that it comprises a structural laminate comprising two or more distinct layers which are joined together. A sheet according to claim 2, characterized in that the laminate comprises alternate polymer layers having film-forming properties and a material containing reactive functional groups. A sheet according to claim 3, characterized in that it comprises a structural laminate comprising two layers of film-forming polymer with a layer of reactive material interspersed between the same and the tissue contact layer. LEAF according to claim 4, characterized in that the reactive material is the same as the material of the tissue contact layer. LEAF according to any one of the preceding claims, characterized in that one or more polymers having film-forming properties are polyesters. LEAF according to claim 6, characterized in that the polyesters are selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactones, polyhydroxyalkanoates, and copolymers and mixtures thereof. LEAF according to claim 7, characterized in that the polyesters are selected from the group consisting of polylactic acid, polyglycolic acid, and copolymers and mixtures thereof. LEAF according to claim 8, characterized in that the polyester is poly (lactide coglycolide). LEAF according to any one of the preceding claims, characterized in that the tissue-reactive groups are selected from the group consisting of imido ester, p-nitrophenyl carbonate, NHS ester, epoxide, isocyanate, acrylate, vinyl sulfone, orthopyridyl. disulfide, maleimide, aldehyde and iodoacetamide. LEAF according to claim 10, characterized in that the tissue reactive functional groups are NHS ester groups. SHEET according to claim 10, characterized in that the fabric-contact layer comprises a tissue-reactive polymer selected from the group consisting of poly (VP-AAc (NHS)) and depoly terpolymer (VP-AAc- AAc (NHS)). Leaf according to any of the preceding claims, characterized in that it has a total thickness of 0.01 to 1 mm. LEAF according to any of the preceding claims, characterized in that it has a total thickness of 0.015 to 0.05 mm. LEAF according to any of the preceding claims, characterized in that the contact layer with the fabric makes up more than 50% of the total thickness of the sheet. LEAF according to claim 1, characterized in that it comprises a structural laminate, the laminate of which comprises η layers of a biodegradable polyester with n-1 layers of material which contain reactive functional groups interspersed between them and a tissue contact layer of the material. reactive, where η has a value of 1, 2, or 3. LEAF according to claim 16, characterized in that the cell-forming polymer is a biodegradable polyester. LEAF according to claim 16, characterized in that it comprises a structural laminate, the laminate of which comprises η layers of a biodegradable polyester with n-1 layers of material which contain reactive functional groups interspersed between them and a tissue contact layer of the material. reactive, where η has a value of 1, 2, or 3. LEAF according to claim 17 or claim 18, characterized in that the polyester is selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactones, polyhydroxyalkanoates, and copolymers and mixtures thereof. LEAF according to claim 19, characterized in that the polyester is selected from the group consisting of polylactic acid, polyglycolic acid, and copolymers and mixtures thereof. LEAF according to claim 20, characterized in that the polyester is poly (lactide-coglycolide). Leaf according to any one of claims 16 to 21, characterized in that the tissue reactive material is poly (VP-AAc-AAc (NHS)). LEAF according to any one of claims 16 to 22, characterized in that the material containing reactive functional groups is poly (VP-AAc-AAc (NHS)). LEAF according to any one of claims 16 to 23, characterized in that η has a value of 2. LEAF according to claim 24, characterized in that the contact layer consists of more than 50% of the total thickness of the sheet. Sheet according to claim 25, characterized in that the fabric contact layer consists of more than 60% of the total thickness of the sheet. A SHEET MANUFACTURING METHOD according to any of the preceding claims, wherein the method comprises the step formation of the layer (s) or structural laminate, followed by the formation of the contact with the fabric. 28. A device suitable for a human or animal implant, wherein the device is characterized in that it contains at least part of its outer surface a coating comprising one or more polymers with film-forming properties, in which at least part of said coating is bonded. a layer of material comprising tissue reactive functional groups. A method of attaching a fabric surface to another fabric or sealing a fabric surface, wherein the method comprises applying to the fabric surface of a sheet according to any one of claims 1 to 26. .