HK1088522B - Resorbable thin membranes - Google Patents

Description

Absorbable film

Background

1. Related application

This application is a partial continuation of U.S. application No. 10/385,399 filed on 3/10/2003 in priority to U.S. application No. 09/805,411 filed on 12/3/2001, a continuation of U.S. patent No. 6,531,146 in the present application, which claims priority to U.S. provisional application No. 60/231,800 filed on 11/9/2002 and U.S. provisional application No. 60/196,869 filed on 10/3/2000. This application also claims priority from U.S. provisional application No. 60/408,393 filed on 9/4/2002 and U.S. provisional application No. 60/399/792 filed on 7/31/2002. The above applications are commonly assigned and the contents of all applications are specifically incorporated herein by reference.

2. Field of the invention

The present invention relates generally to medical implants, and more particularly to absorbable membranes and methods of using the membranes.

3. Description of the related Art

A major clinical problem associated with surgical repair or inflammatory diseases is adhesions that occur during the initial stages of the healing process after surgery or disease. Adhesions are symptoms associated with the formation of abnormal tissue connections. For example, the connection may impair bodily function, produce infertility, block the intestine and other parts of the gastrointestinal tract (ileus), and produce general discomfort, such as pelvic pain. The symptoms may be life threatening in certain situations. The most common form of adhesion that occurs post-operatively occurs as a result of surgical intervention, however, adhesion may also occur as a result of other processes or events, such as pelvic inflammatory disease, mechanical injury, radiation therapy, and the presence of foreign materials.

Various attempts have been made to prevent post-operative adhesions. For example, peritoneal lavage, heparinized solutions, the use of procoagulants, improvements in surgical techniques such as the use of microscopic or laparoscopic surgical techniques, the elimination of talc from surgical gloves, the use of smaller sutures, and the use of physical barriers (membranes, gels or solutions) have been attempted with the aim of reducing serosal surface adhesion. Unfortunately, the industry has met with very limited success using the above-described methods. Various forms of bulking materials, such as membranes and viscous intraperitoneal solutions designed to limit tissue apposition, have also met with limited success. The barrier material may include a cellulosic barrier, a polytetrafluoroethylene material, and a dextran solution.

U.S. Pat. No. 5,795,584 to Tokahura et al discloses anti-adhesion or scar tissue reduction films or membranes, while U.S. Pat. No. 6,136,333 to Cohn et al discloses similar structures. In Tokahura et al, a bioabsorbable polymer is copolymerized with a suitable carbonate and then formed into a non-porous, single layer adhesion barrier, such as a film. In the Cohn et al patent, a polymeric hydrogel for anti-blocking is made without crosslinking through the use of urethane chemicals. However, these patents all involve relatively complex chemical formulas and/or reactions that create specific structures for surgical adhesion barriers. There remains a need for improved films.

Disclosure of Invention

The present invention provides improved resorbable membranes that may be used in a variety of surgical applications, for example, to delay or prevent tissue adhesions and reduce scarring. In addition, the polymers and copolymers of the present invention require relatively simple chemical reactions and formulations.

According to one feature of the present invention, a resorbable thin membrane is provided that includes a substantially uniform composition of amorphous polylactide, e.g., 70: 30 poly (L-lactide-co-D, L-lactide).

The amorphous polylactide membrane can be extruded with an initial, higher viscosity characteristic that is equal to or greater than about 5.5 g/dL. The initial viscosity characteristics may facilitate reliable formation of the film, including reducing the occurrence of, for example, film cracking or tearing during extrusion. The viscosity characteristics of the film typically decrease after processing and sterilization. According to other aspects of the invention, other higher viscosity properties, such as a viscosity property above 4g/dL, may be used in order to increase the strength of the amorphous polylactide material during the extrusion process. The extrusion process provides a film having a biased molecular orientation.

According to another feature of the present invention, the membrane having a first substantially smooth surface and a second substantially smooth surface is non-porous and has a thickness, measured between the first substantially smooth surface and the second substantially smooth surface, of from about 0.01mm to about 0.300 mm. The membrane includes at least one thicker portion which may form at least a portion of an edge of the membrane. Thus, the membrane has a varying cross-sectional thickness.

Any feature or combination of features disclosed herein is included within the scope of the present invention provided that the features are included in any such combination without conflict, as would be understood by one of ordinary skill in the art from the present specification, and knowledge of one of ordinary skill in the art. Other advantages and aspects of the invention will become apparent from the following detailed description and claims.

A resorbable thin membrane comprising a homogeneous composition comprising a polymer capable of resorbing into the mammalian body within a period of less than 24 months after initial implantation of the membrane into the mammalian body, wherein the polymer has a biased molecular orientation that is biased toward at least one axis and has a viscosity property greater than 1g/dL, wherein the membrane has a first smooth surface and a second smooth surface, and wherein the membrane is non-porous and has a thickness of 0.001mm to 0.300mm measured between the first and second smooth surfaces.

The polymer comprises an amorphous polymer.

The polymer comprises polylactide.

The polylactide comprises a copolymer of L-lactide and D, L-lactide.

The polymer comprises a copolymer of lactide and epsilon caprolactone.

The molecular orientation of the polymer is biased toward one axis.

The molecular orientation of the polymer is biased towards two axes.

The thickness is 0.010mm-0.100 mm.

The thickness of the material is 0.015mm-0.025 mm.

The thickness is 0.020 mm.

The film has a glass transition temperature and the thickness of the film increases by at least a factor of 5 when the film is heated to its glass transition temperature.

The film has a glass transition temperature and the thickness of the film increases by at least a factor of 10 when the film is heated to its glass transition temperature.

It is impregnated with an additive selected from the group consisting of: chemotactic substances for influencing cell migration, inhibitory substances for influencing cell migration, mitogenic growth factors for influencing cell proliferation and growth factors for influencing cell differentiation.

It is contained in a sealed sterile package.

And at least one thick portion, each thick portion having a length equal to or shorter than the maximum length of the film, a width greater than 0.5mm, and a thickness greater than 2 times the central thickness of the film.

The thick portion protrudes from the two smooth surfaces and forms at least a portion of the edge of the membrane.

The first thick portion forms at least a portion of a first edge of the membrane and the second thick portion forms at least a portion of a second edge of the membrane.

The thickness of the film increases by more than a factor of 2 when the film is heated to its glass transition temperature.

Further comprising a plurality of holes distributed along the thick portion.

Also included are a plurality of apertures distributed along an edge of the film.

The viscosity characteristic is more than 2 g/dL.

The viscosity characteristic was 3 g/dL.

It has non-uniform shrinkage characteristics.

It has directional shrinkage characteristics.

Resorbable thin membranes comprising a homogeneous composition of a polymer extruded into a membrane: is absorbable into a mammalian body in less than 24 months after first implantation in the mammalian body, has a viscosity characteristic of greater than 1g/dL, and further has a first smooth surface and a second smooth surface, and has a thickness, measured between the first and second smooth surfaces, of from 0.010mm to 0.030 mm.

The polymer comprises an amorphous polymer.

Further comprising at least one thick portion having a length equal to or shorter than the maximum length of the thin film, a width greater than 0.5mm, and a thickness 2 times greater than that of a portion of the thin film other than the at least one thick portion.

The thick portion protrudes from the two smooth surfaces and forms at least a portion of the edge of the membrane.

The first thick portion forms at least a portion of a first edge of the membrane and the second thick portion forms at least a portion of a second edge of the membrane.

The thick portion is effective to provide rigidity to the membrane.

Further comprising a plurality of holes distributed along the thick portion.

The membrane is non-porous and comprises polylactide.

A resorbable thin membrane comprising:

a first smooth surface and a second smooth surface, wherein the thickness between the first and second smooth surfaces is 0.01mm to 0.300 mm; and

at least one thick portion having a length equal to or shorter than a maximum length of the thin film, a width greater than 0.5mm, and a thickness 2 times greater than a thickness of the thin film at a portion other than the at least one thick portion, and having a viscosity characteristic equivalent to a pre-extrusion and pre-sterilization viscosity characteristic greater than 4 g/dL.

The thick portion protrudes from the two smooth surfaces and forms at least a portion of the edge of the membrane.

Including a first thick portion forming at least a portion of a first edge of the membrane and a second thick portion forming at least a portion of a second edge of the membrane.

Further comprising a plurality of holes distributed along the thick portion.

The at least one thick portion includes a plurality of thick portions, and the thin film is made of an amorphous polymer.

The polymer comprises polylactide.

The polymer includes a copolymer of L-lactide and D, L-lactide.

The polymer includes caprolactone.

The polymer has a biased molecular orientation toward one axis.

The polymer has a biased molecular orientation towards two axes.

The thickness between the first and second smooth surfaces is between 0.015mm and 0.025 mm.

The film has a glass transition temperature and the thickness of the film increases by at least a factor of 5 when the film is heated to its glass transition temperature.

The film has a glass transition temperature and the thickness of the film increases by at least a factor of 10 when the film is heated to its glass transition temperature.

The membrane is liquid impermeable.

Further comprising an additive impregnated in the film, the additive selected from one of the following groups: chemotactic substances for influencing cell migration, inhibitory substances for influencing cell migration, mitogenic growth factors for influencing cell proliferation and growth factors for influencing cell differentiation.

It is contained in a sealed sterile package.

The viscosity characteristic is more than 1 g/dL.

The viscosity characteristic is more than 2 g/dL.

Drawings

FIG. 1a shows a membrane in which the molecular orientation of amorphous polylactide is biased in one axis;

figure 1b shows a membrane wherein the molecular orientation of the amorphous polylactide is biased towards two axes;

FIG. 2a shows a membrane with a thick portion;

FIG. 2b shows a membrane having a thick portion which forms part of the edge of the membrane;

FIG. 2c shows a membrane having a thick portion constituting an edge of the membrane;

figures 2d and 2e show a membrane having more than one thick portion on it.

FIG. 2f shows a membrane having a thick portion with holes;

FIG. 3a shows a laminotomy procedure wherein a portion of the posterior arch (lamina) of the vertebra is surgically removed;

FIG. 3b is an enlarged schematic view of FIG. 3 a;

FIG. 3c shows a thin membrane applied over the exiting nerve root of the spinal chord in accordance with a first pre-formed embodiment of the present invention;

FIG. 4 shows a thin membrane applied to two exiting nerve roots of the spinal chord in accordance with a second pre-formed embodiment of the present invention; and

figure 5 shows a thin membrane applied to four exiting nerve roots of a spinal chord according to a third pre-formed embodiment of the present invention.

Description of the preferred embodiments of the invention

Reference will now be made in detail to the preferred embodiments of the present invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same or similar reference numbers are used in the drawings and the description to refer to the same or like parts. It should be noted that the drawings are in simplified form and are not to precise scale. For convenience and clarity only, directional designations such as top, bottom, left, right, upward, downward, above, below, bottom, rear, and front are used with respect to the drawings and should not be construed as limiting the scope of the invention in any way.

While the description herein refers to certain illustrative embodiments, it is to be understood that these embodiments are provided by way of example and not by way of limitation. While exemplary embodiments have been discussed, the following detailed description is intended to be construed to cover all modifications, alterations, and improvements that fall within the spirit and scope of the invention as defined by the appended claims.

A resorbable thin membrane in accordance with one embodiment of the present invention includes a substantially homogeneous composition including polylactide. In the illustrated embodiments, the polylactide is amorphous and/or has a skewed molecular orientation. Amorphous polylactides are those which do not give a clear X-ray diffraction pattern in this context. Such polymers may include regions where few, if any, structural units are arranged in a three-dimensional regular (crystalline) order; and their structure may be present in a disordered form of long molecules, where there may be groups of chain moieties that are substantially parallel, but not sufficiently ordered. In one embodiment, the phrase "substantially amorphous" may be substituted herein for the term amorphous, while in another embodiment, the phrase "somewhat amorphous" or "slightly amorphous" may be substituted herein for the term amorphous.

The barrier membrane of the present invention may be formed from a variety of biodegradable materials, such as absorbable polymers. Non-limiting polymers that may be used to produce the barrier membranes of the present invention, according to one embodiment of the present invention, include polymers (e.g., copolymers) of lactide (L, D, DL, or combinations thereof), glycolide, trimethylene carbonate, caprolactone and/or physical and chemical combinations thereof. In one embodiment, the barrier membrane comprises polylactides, which may be copolymers of L-lactide and D, L-lactide. For example, the copolymer may include about 60-80% L-lactide and about 20-40% D, L-lactide, and in a preferred embodiment, the copolymer includes 70: 30 poly (L-lactide-co-D, L-lactide). In one embodiment, the barrier membrane is made from a polymer (e.g., a homopolymer and/or copolymer) derived from one or more cyclic esters, such as lactide (i.e., L, D, DL, or a combination thereof), epsilon-caprolactone and glycolide. For example, the barrier film may comprise from about 1 to 99% epsilon-caprolactone in one embodiment, or from 20 to 40% epsilon-caprolactone in another embodiment. In one example, the barrier membrane comprises 65: 35 poly (L-lactide-co-epsilon-caprolactone). In other embodiments, butyrolactone, valerolactone, or dimethylpropanolactone may be used with or in place of epsilon-caprolactone. In another embodiment, the barrier membrane may comprise a copolymer comprising lactide and glycolide, which is capable of being absorbed into the body more rapidly than the poly (L-lactide-co-D, L-lactide) described above.

In the preferred embodiment, the film may be produced by extrusion, for example, as is known in the art. The extrusion process is preferably used to efficiently produce the film. In addition, the films produced by such extrusion techniques may be free of solvent residue in the film and may also provide molecular biasing, including a predetermined molecular biasing. In a preferred embodiment of the invention, uniaxial extrusion may be used to produce the films of the invention. In a modified embodiment, a biaxial extrusion process may be used to produce the film. In one embodiment, a combination blend containing an amorphous absorbable polymer may be extruded to produce the membranes of the present invention, such as an amorphous lactide polymer, which may be, for example, poly-L-lactide or more preferably poly (L-lactide-co-D, L-lactide). In one embodiment, poly (L-lactide-co-D, L-lactide) 70: 30 monomer LR708 (produced and supplied by Boehringer Ingelheim KG, Germany) is extruded to produce the membranes of the present invention.

According to one aspect of the invention, the film has a viscosity characteristic in a specific range. As used herein, "viscosity property" is an indication of the viscosity of a dilute solution of polymer, expressed as the ratio of the natural logarithm of the relative viscosity to the concentration in grams of polymer per 100 milliliters of solvent. The viscosity characteristics are understood by the person skilled in the art as the intrinsic viscosity of the solution as is customary in the art. In one embodiment, the films of the present invention have a molecular bias, indicating that they are produced by extrusion techniques and have higher viscosity characteristics.

In accordance with one aspect of the present invention, it has been found that amorphous polylactide compositions having a pre-extrusion viscosity property of greater than about 5g/dL can be extruded to produce thinner membranes of the present invention. According to other aspects of the invention, other higher viscosity properties, such as viscosity properties in excess of 4g/dL, may be used in order to increase the strength of the amorphous polylactide material during, for example, an extrusion process.

The initially high (i.e. pre-extrusion) viscosity characteristics of the amorphous polylactide may facilitate reliable shaping of the membrane, for example, including reducing the occurrence of weakening, breaking or tearing of the membrane during the extrusion process. Although the viscosity characteristics of the film are low after processing and sterilization, the initial higher viscosity characteristics of the film may facilitate extrusion down to a thickness of a fraction of a millimeter. For example, it has been found that amorphous polylactide polymers having an initial (pre-extrusion) viscosity property in the range of about 5g/dL to about 7g/dL can be extruded into films having a thickness of about 0.02mm and the resulting viscosity property is about 2.5g/dL to about 3.5g/dL, while employing sterilization techniques that do not significantly alter the viscosity property of the material. In one embodiment, ethylene oxide is used to sterilize the film. It is believed that ethylene oxide does not cause a significant reduction in the viscosity characteristics of the film. In other embodiments where other sterilization techniques, such as electron beam, are used, the resulting viscosity property may be from about 1.25g/dL to about 1.75, rather than from about 2.5g/dL to about 3.5 g/dL. In other embodiments, such as sterilization using electron beams, the extruded film has a viscosity property greater than about 1 g/dL. In one embodiment, the viscosity property of the film is greater than about 2 g/dL. Preferably, the films of the present invention have a viscosity characteristic of from about 2.7g/dL to about 3.5 g/dL.

According to one aspect of the invention, the molecular orientation of the amorphous polylactide is biased. The extrusion process described above can provide such biased molecular orientation. The biased molecular orientation may be predetermined such that a suitable process, such as a suitable extrusion process, may be used to produce the films disclosed herein. In one embodiment, the polymer chains of the film are substantially aligned along one axis, as shown in FIG. 1 a. For example, more than about 65%, preferably more than about 80%, of the polymer chains or segments of polymer chains are aligned along the axis 101 of the film 100.

In one embodiment, the polymer chains are substantially aligned along two axes. Fig. 1b shows a membrane 102 having a first axis 103 and a second axis 104. The polymers are aligned along the axis. In such embodiments, the polymer chains or segments of polymer chains are more than about 50%, preferably more than about 90%, substantially aligned along one of these two axes. In one embodiment, the aligned polymers are in equal proportion between the first axis 103 and the second axis 104. In another embodiment, there are more polymers arranged on the first axis 103 than on the second axis 104. For example, about 45% of the polymers are aligned on the first axis and 55% of the polymers are aligned on the second axis. In one embodiment, the axes form an angle 106 of less than 80 degrees. Preferably, the axes form an angle 106 of less than about 45 degrees, more preferably less than 30 degrees, and more preferably less than 20 degrees.

The molecular orientation of the amorphous polylactide can impart various physical properties to the film. For example, a film having a biased molecular orientation may shrink in a direction substantially perpendicular to the axis when the film is subjected to a heat treatment sufficient to heat the film to its glass transition temperature. As shown in fig. 1a, when film 100 having a biased molecular orientation is subjected to a heat treatment, the direction of shrinkage 105 may be substantially perpendicular to axis 101. In addition, the skewed molecular orientation allows for control or selective control of the direction of shrinkage when the film is heated. This feature may be advantageous where a particular configuration and size is required for implanting the membrane.

In one embodiment, during extrusion, a film is output through an aperture having a first thickness and then stretched to a second thickness, wherein the first thickness is greater than the second thickness. The first thickness may be two times greater than the second thickness, and more preferably five times greater than the second thickness. More preferably ten times greater than the second thickness. Thus, when the treated and sterilized film is subsequently heated to its glass transition temperature, its thickness will or may return to the first thickness.

In one embodiment, the film of the present invention does not shrink uniformly in all directions when subjected to heat treatment. Preferably, the film of the present invention shrinks significantly in a direction perpendicular to the molecular orientation axis, but not significantly in a direction parallel to the molecular orientation axis, upon heating the film to the glass transition temperature. For example, the film of the present invention may shrink by about 5% to about 30% in a direction perpendicular to the molecular orientation axis, and may shrink by about 1% to about 5% in a direction parallel to the molecular orientation axis. In one example, when the processed and treated film is subsequently heated to its glass transition temperature, it will shrink in a direction substantially perpendicular to the alignment axis (e.g., 101) or axes (e.g., 103, 104), the amount of shrinkage being proportional to the amount of stretching in the initial extrusion process. As embodied by this embodiment, shrinkage in a direction perpendicular to the alignment axis continues until the film returns from the second thickness to the first thickness.

The film of the present invention may have at least one substantially smooth surface. Preferably, the film of the present invention has two (opposing) substantially smooth surfaces. The film of the present invention has a thickness, as measured between the opposing surfaces, of from about 0.01mm to about 0.3mm, more preferably from about 0.01mm to about 0.1 mm. In a preferred embodiment, the films of the present invention have a thickness of from about 0.015mm to about 0.025 mm. In another preferred embodiment, the film of the present invention has a thickness of about 0.02 mm.

The film of the present invention may further comprise at least one thick portion protruding from at least one of the two substantially smooth surfaces. In a preferred embodiment, the at least one thick portion protrudes from the two substantially smooth surfaces. In other words, the membrane may comprise a plurality of portions or portions having different thicknesses. In one embodiment, the film includes a first portion having a first thickness, and a second portion having a second thickness, wherein the first thickness is greater than the second thickness. The first portion may be located away from the edge of the film or the first portion may be located at the edge of the film. In addition, the first portion has a length that does not exceed the length or width of the film. In certain embodiments, the length is less than the length and width of the film.

The output orifice of the extrusion device may have a shape corresponding to the cross-section of the membrane. For example, to produce a film having thicker portions at two opposing edges of the film, the outlet of the extrusion device may comprise a generally rectangular shape having a width and a height, wherein the shape is varied by the height of the outlet being greater at the opposing edges of the outlet than at a location between the two opposing edges of the outlet. In this configuration, the profile of the height across the width of the outlet opening substantially corresponds to the profile of the thickness across the width of the film. In other embodiments, for example, a membrane having thick portions on opposite edges thereof may be produced using an extrusion apparatus having a rectangular output port. In other embodiments, the thick portion may be formed by means such as machining, which may be performed alone or in combination with the extrusion process discussed above. In addition to the above process, which is capable of producing a uniaxial molecular alignment in which, for example, about 80% or more of the molecular alignment of the film is in one direction, it is also possible to produce a biaxially oriented film by using, for example, a circular outlet through which high-pressure air is blown into the tubular film being output.

Preferably, the thick portion is effective to provide a bonding function with the membrane. In a modified embodiment, the thick portion is effective to provide rigidity to at least a portion of the membrane. In one embodiment, each thick portion has a length equal to or less than the length of the film, a width of from about 0.5mm to about 25mm (and, in one embodiment, no greater than the width of the film), and a thickness of from about 2 to about 10 times greater than the thickness of the film. For example, fig. 2a shows a thick portion 115. In this figure, the length 113 of the thick portion 115 is equal to the length of the membrane 112, the width of the thick portion 111 is less than the width of the membrane 114, and the thickness of the thick portion 116 is approximately three times the thickness of the membrane 117. For purposes of the description herein, the thick portion 115 corresponds to a first portion having a first thickness, while the remaining portion of the illustrated membrane 112 corresponds to a second portion having a second thickness that is less than the first thickness.

In one embodiment, the thick portion has a length less than the length of the membrane. For example, FIG. 2b shows a membrane 120 that includes a thick portion 121. The thick portion 122 has a length less than the length of the membrane 123. The thick portion 122 is also smaller than the width of the membrane 123. In one embodiment, the thick portion forms a portion of the edge of the film, or forms the entire edge of the film. For example, FIG. 2b shows a thick portion forming a portion of the edge of the membrane 124. Fig. 2c shows an edge 130 having four edges 132, one of which is formed by a thick portion 131. In one embodiment, the membrane includes more than one thick portion. For example, FIG. 2d shows membrane 140 having a first thick portion 141 forming a portion of a first edge 143, and a second thick portion 142 forming a portion of a second edge 144.

Preferred membranes of the invention comprise a substantially homogeneous composition of amorphous polylactide, such as PLLA. In addition, the amorphous polylactide has a biased molecular orientation in the film due to extrusion. In addition, the membrane includes first and second thick portions, each thick portion having a width of about 5mm to about 25mm and a thickness of about 0.070 mm. The thickness of the film measured between the two surfaces was about 0.02 mm. The film has a viscosity property greater than about 2g/dL, corresponding to a pre-extrusion and pre-sterilization viscosity property greater than about 4 g/dL. Preferably, the films of the present invention have a viscosity property greater than about 2.75g/dL, which corresponds to a pre-extrusion and pre-sterilization viscosity property greater than about 5.5 g/dL. Figure 2e shows an embodiment of a membrane 150 having a first thick portion 151 forming a first edge 153 and a second thick portion 152 forming a second edge 154. In other modified embodiments, other thick portions may be formed at other edges or portions of the film 124. For example, four thick portions may be formed on four respective edges of a rectangular membrane.

The film of the present invention may further comprise a plurality of apertures distributed along at least one edge of the film. Preferably, the holes pass through the membrane. In one embodiment, the rim has an aperture formed by at least one thick portion. For example, FIG. 2f shows membrane 160 having a first thick portion 161 and a second thick portion 162. The thick portion has a hole along its length. For example, the holes may facilitate suturing the membrane to tissue.

In terms of bonding, various means for bonding the membrane to structures such as muscle tissue, other soft tissue, or bone are included, and these means may be used with or without holes. However, according to a preferred embodiment, the bonding means is implemented on a substantially thick portion of the membrane, although this is not essential. In addition to sutures, staples may be used to attach the membrane to the paravertebral muscles. As another example, the thin membrane may be secured to the vertebrae with absorbable bone screws or tacks. Pressing or folding the film material into anatomical crevices may be sufficient in some instances to fix its position. Adhesives such as fibrin sealant, or absorbable cyanoacrylate adhesive may also be used to secure the membrane, either alone or in combination with the above attachment means. In a preferred embodiment, the above-described joining method is applied to the thick portion.

For example, each thick portion on the membrane may have a width of about 0.5mm to about 25 mm. In one embodiment, the thick portion is about 5 to about 25mm wide, which may be used for suturing purposes. In another embodiment, the thick portion has a width of about 0.5mm, which can be used for heat bonding as described below. According to one aspect of the invention, the thick portion may be heat bonded, such as by using a bipolar electrocautery device, ultrasonic welding, or the like, directly to tissue, such as the dura of the spinal chord 30 and the exiting nerve root 32 (FIG. 3 a). Such a device can be used to heat various parts of the film other than the thick portions, such as the non-thick edges and points in the middle, to a temperature at least above the glass transition temperature of the film, and preferably above its softening point. For example, PLLA has a glass transition temperature of about 55 ℃ and a softening point temperature of greater than 110 ℃, and the material is heated with the tissue in its vicinity so that the two components bond together at their interface. In another embodiment, a thick portion or other portion of the membrane may be heat bonded or sealed directly to one or both of the two vertebrae 20 and 22 (fig. 3a), or to muscle or other soft tissue. In another embodiment, a thick portion or other portion of the film may be heat bonded or sealed directly to itself during application, for example, wherein the film is wrapped around a structure and then heat bonded to itself. In addition, the technique of heat sealing the film to itself or body tissue may be combined with another bonding method for enhanced anchoring. For example, the membrane material may be temporarily secured using an electrocautery device with two or more heat sealed points (i.e., heat welding), and then sutures, staples, or glue may be added to secure the membrane in place.

The film of the present invention may be more effective than other films because it is very smooth and non-porous. For example, the lack of porosity acts to form a barrier that does not allow the tissue to interact. The non-porous and smooth nature of the film reduces tissue turbulence, enhances tissue guidance, and reduces scarring. In addition, the smooth, discontinuous surface of the membrane may facilitate movement of the dura and local tissue through the site, thereby reducing friction and wear that may induce scar tissue formation.

As used herein, the term "non-porous" refers to a material that is substantially water impermeable and, according to a preferred embodiment, fluid impermeable. However, in a modified embodiment of the invention, the membrane of the invention may be microporous (i.e., fluid permeable, but cell impermeable) to the extent that, for example, the pores do not significantly disrupt the smoothness of the surface of the resorbable membrane, thereby causing scarring of the tissue. In a significantly improved embodiment of limited use, pores that are cell permeable, but vessel impermeable, can be produced and used.

As embodied by the present invention, many thin film thicknesses are sufficient to form a profile even without heating to the glass transition temperature. In one embodiment, the films of the present invention are capable of being absorbed into a mammal within about 18 to about 24 months from the initial implantation of the film into the mammal. The films can be used for a variety of surgical purposes, including: surgical repair of infraorbital fractures, surgical repair of septal and perforated eardrum membranes, as protective coverings to promote osteogenesis, surgical repair of urethral anatomy, and repair of urethral strictures, prevention of osseointegration in completed cranial fusion and corrective surgery of forearm fractures, reduction of soft tissue fibrosis or bony growth, as temporary coverings for prenatal ruptured umbilicus, guided tissue regeneration at the teeth and gingival margin, tympanic membrane repair, dural covering and nerve repair, cardiovascular repair, hernia repair, tendon anastomosis, temporary seam spacers, wound dressings, scar coverings, and as coverings for abdominal fractures during staged repair. The films of the present invention are particularly useful in preventing abnormal fibrotic binding of tissues together after surgery, which can lead to abnormal scarring and interfere with normal physiological function. In some instances, the scarring may force and/or interfere with augmentation, correction, or other surgical procedures.

For example, there is evidence that epidural adhesions are a possible factor in the failure of back surgery. Epidural fibrosis may occur in spinal injuries or as a surgical complication following surgery. The dense scar formation on the dura and the peripheral nerve roots has previously been described as a "laminotomy membrane" and has been suggested to make subsequent spinal surgery technically more difficult. For example, during a laminectomy procedure, the membrane of the present invention is preferably inserted between the dural sleeve and the paravertebral musculature after the laminotomy and is conveniently deformed to enclose the exposed lamina bone marrow factor. It is believed that placement of the thin film material as a barrier between the paravertebral musculature and the epidural space reduces cell migration and vascular invasion of the epidural space from the overlying muscle and adjacent exposed cancellous bone. In addition, tests have shown that the film of the present invention does not interfere with normal late wound healing, while at the same time inhibiting undesirable adhesions and scar formation.

The very thin construction of the membrane is believed to significantly increase the rate of absorption of the membrane compared to the rate of absorption of a thicker membrane implant of the same material. However, it is believed that absorption of the membrane into the body too quickly can result in an undesirable decrease in local pH levels, thereby causing/exacerbating, for example, local inflammation, discomfort and/or foreign antibody responses. In addition, the non-uniformity of the resulting film (e.g., crumbling, breaking, roughening, or lumpy surface), prematurely degrades, may undesirably result in tissue turbulence between the tissues, e.g., leading to potential tissue inflammation and scarring before proper healing is achieved. It is believed that the film of the present invention having a thickness of about 0.200mm or less is able to maintain its structural integrity for more than 3 weeks, and more preferably for a period of at least 7 weeks, prior to degradation, in order to enable and optimize the anti-scarring function. The film does not degrade at an accelerated rate compared to a thicker film of the same material, to the extent that the film is able to maintain its structural integrity for more than 6 months, more preferably at least 1 year, before significantly degrading, in order to achieve and optimize the anti-scarring function. Therefore, the polylactide resorbable polymer membranes in accordance with this aspect of the invention are designed to be resorbed into the body at a slower rate.

It is believed that reducing acidity levels and/or tissue turbulence, as well as any accompanying inflammation (e.g., swelling) at the post-operative site, is particularly important in spinal surgery, which is often performed for the special purpose of alleviating inflammation-induced discomfort. For example, it is believed that neural tissue may be particularly sensitive to slightly elevated acidity levels and inflammation. During a typical spinal procedure, such as a laminotomy, a portion of the lamina structure is removed from a patient's vertebrae so as to, for example, provide access to the spinal column and/or disc.

The film can be provided in a rectangular shape, for example, several centimeters on each side of the rectangle, or cut and formed into a particular shape, configuration and size by the manufacturer prior to packaging and sterilization. In modified embodiments, various known formulations and copolymers, for example, polylactide, may affect the physical properties of the membrane. The film of the present invention is flexible enough to wrap around anatomical structures, however, some heating in a hot water bath may be necessary for thicker structures. In a modified embodiment, certain polylactides, which may be softened by formation with other copolymers and/or other monomers, e.g., epsilon-caprolactone, may become harder and more brittle at thicknesses in excess of 0.25mm, e.g., film formation may be practiced. Further, according to another aspect of the present invention, the thin film may include at least one of a chemotactic substance for influencing cell migration, an inhibitory substance for influencing cell migration, a mitogenic growth factor for influencing cell separation, and a growth factor for influencing cell differentiation. The substance may be impregnated into the film, but may also be coated on one or more surfaces of the film. In addition, the substance can be contained on or within the membrane in a separate unit effective to facilitate selective release of the substance after insertion of the membrane into the patient.

Fig. 3a shows a laminotomy procedure in which two vertebrae 20 and 22 are separated and fixed using screws 24 and rods 26. A portion of the lamina has been removed leaving a window 28 (shown as a rectangle in phantom) in the vertebra 22. Fig. 3b is an enlarged view of the window 28 in the lamina of the vertebra 22. The spinal chord 30 and the exiting nerve root 32 are thus exposed. In accordance with the present invention, the membrane is applied over the dura of the spinal chord 30 and the exiting nerve root 32 to reduce or eliminate post-operative scarring near the exiting nerve root 32.

Referring to fig. 3c, a first welding flange 36 and a second welding flange 38 are formed on the pre-formed film 34. These welding flanges may be made as thick portions or have thick portions only along their edges. Additionally, in modified embodiments, the thick portion may be formed on other edges of the films disclosed below, formed on other portions of the films, and/or any combination thereof. The trunk portion 40 overlies the spinal chord 30, and the branch portions 42 overlie the exiting nerve root 32. The first welding flange 36 is formed by a first slit 44 and a second slit 46, while the second welding flange 38 is formed by a first slit 48 and a second slit 50. In use, the preformed thin film 34 is placed over the spinal chord 30 and the exiting nerve root 32, and then the first and second welding flanges 36, 38 are bent at least partially around the exiting nerve root. The rounded ends 52 of the branch portions 42 engage the portions of the exiting nerve root 32 that are further from the spinal chord 30. As embodied in this embodiment, the first welding flange 36 and the second welding flange are wrapped around, and preferably under (i.e., behind) the exiting nerve root 32. In the preferred embodiment, the first welding flange 36 is then welded to the second welding flange 38. The flanges are preferably cut to wrap entirely around the exiting nerve root 32 and cover each other, and the first welding flange 36 may be sewn to the second welding flange 38 alone or in addition to the heat welding step to secure the first welding flange 36 to the second welding flange 38. In another embodiment, neither heat welding nor suturing is used, but rather the flange is merely partially or completely crimped around the exiting nerve root 32 (depending on the size of the nerve root 32). Where sutures are used, the preformed membrane 34 may be preformed and wrapped with optional suture holes 60. The edges 64 and 66 are then bonded to the spinal chord 30, preferably by heat welding. A third welding flange 72 is formed by the two edges 68 and 70. The fourth welding flange 74 is formed by the cut-outs 76 and 78, while the fifth welding flange 80 is formed by the cut-outs 82 and 84. The weld flanges can be secured in a manner similar to that disclosed in connection with weld flanges 36 and 38. The heated weld may also be secured along other edges of the preformed film 34 and along its surface. In addition, incisions may be formed in the membranes of the present invention, for example, on the ends 64 and 66 in modified-shape embodiments, to accommodate, for example, spinal cord management.

Figure 4 shows a thin membrane applied to two exiting nerve roots 32 and 98 of the spinal chord according to another preformed embodiment of the present invention. Figure 5 shows a thin membrane similar to that of figure 4 but adapted for application to four exiting nerve roots of a spinal chord according to another pre-formed embodiment of the present invention. For example, branch portion 100 is similar in construction and operation to branch portion 42 of the embodiment of FIG. 3, and other branch portions 102 are formed to receive exiting nerve roots 98. Similar components are shown in fig. 5 with reference numerals 100a, 102a, 100b and 102 c. Other structures for accommodating different anatomical structures may be produced. For example, the structure may be designed to be made, e.g., a tapered structure, to bond around the base portion with the projections extending through the center of the membrane. Suture perforations may be provided around the circumference of the membrane, and may also include cell and vessel permeable pores.

According to the invention, the preformed film is preformed and sealed in sterile packaging for subsequent use by a surgeon. Since it is an object of the film of the invention to reduce sharp edges and surfaces, it is believed that the preforming of the film helps to improve, albeit to a lesser extent, the smoothness of the edges to reduce friction, tissue turbulence and inflammation. That is, the surface of the membrane and any sharp edges are believed to be slightly degraded by the membrane's prolonged exposure to moisture in the air, thereby forming a more rounded edge, which is believed to be a minor effect. In addition, the initial heating of the pre-cut film to the glass transition temperature prior to implantation can further round any sharp edges. In addition, the very thin films of the present invention may be particularly susceptible to such phenomena and may be subject to tearing or loss due to handling to a greater extent, thus making the preforming of the film advantageous for maintaining its integrity.

The above embodiments have been provided by way of example and the invention is not limited to these examples. While the above description is a complete description of the preferred embodiments of the invention, various changes, modifications, and equivalents may be used. In addition, it will be apparent that certain other modifications may be practiced within the scope of the appended claims.

Claims (50)

1. A resorbable thin membrane comprising a homogeneous composition comprising a polymer capable of resorbing into the mammalian body within a period of less than 24 months after initial implantation of the membrane into the mammalian body, wherein the polymer has a biased molecular orientation that is biased toward at least one axis and has a viscosity property greater than 1g/dL, wherein the membrane has a first smooth surface and a second smooth surface, and wherein the membrane is non-porous and has a thickness of 0.001mm to 0.300mm measured between the first and second smooth surfaces.

2. The film of claim 1, wherein the polymer comprises an amorphous polymer.

3. The membrane of claim 1 wherein the polymer comprises polylactide.

4. The membrane of claim 3 wherein the polylactide comprises a copolymer of L-lactide and D, L-lactide.

5. The membrane of claim 1 wherein the polymer comprises a copolymer of lactide and epsilon caprolactone.

6. The film of claim 3 wherein the molecular orientation of the polymer is biased toward one axis.

7. The film of claim 3 wherein the molecular orientation of the polymer is biased toward two axes.

8. The film of claim 3 having a thickness of from 0.010mm to 0.100 mm.

9. The film of claim 3 having a thickness of from 0.015mm to 0.025 mm.

10. The film of claim 3 having a thickness of 0.020 mm.

11. The film of claim 3, wherein the film has a glass transition temperature and the thickness of the film increases by at least a factor of 5 upon heating the film to its glass transition temperature.

12. The film of claim 3, wherein the film has a glass transition temperature and the thickness of the film increases by at least a factor of 10 upon heating the film to its glass transition temperature.

13. The film of claim 3 which is impregnated with an additive selected from the group consisting of: chemotactic substances for influencing cell migration, inhibitory substances for influencing cell migration, mitogenic growth factors for influencing cell proliferation and growth factors for influencing cell differentiation.

14. The film of claim 3, which is contained in a sealed sterile package.

15. The membrane of claim 3 further having at least one thick portion, each thick portion having a length equal to or shorter than the maximum length of the membrane, a width greater than 0.5mm, and a thickness greater than 2 times the thickness of the center of the membrane.

16. The membrane of claim 15 wherein the thick portion protrudes from the two smooth surfaces and forms at least a portion of an edge of the membrane.

17. The membrane of claim 15 wherein the first thick portion forms at least a portion of a first edge of the membrane and the second thick portion forms at least a portion of a second edge of the membrane.

18. The film of claim 15 wherein the thickness of the film increases by a factor of more than 2 when the film is heated to its glass transition temperature.

19. The membrane of claim 16 further comprising a plurality of holes distributed along the thick portion.

20. The film of claim 3, further comprising a plurality of apertures distributed along an edge of the film.

21. The membrane of claim 3 having a viscosity property greater than 2 g/dL.

22. The membrane of claim 3 having a viscosity characteristic of 3 g/dL.

23. The film of claim 3 having non-uniform shrinkage characteristics.

24. The film of claim 3 having oriented shrink properties.

25. Resorbable thin membranes comprising a homogeneous composition of a polymer extruded into a membrane: is absorbable into a mammalian body in less than 24 months after first implantation in the mammalian body, has a viscosity characteristic of greater than 1g/dL, and further has a first smooth surface and a second smooth surface, and has a thickness, measured between the first and second smooth surfaces, of from 0.010mm to 0.030 mm.

26. The film of claim 25, wherein the polymer comprises an amorphous polymer.

27. The membrane of claim 25 further comprising at least one thick portion having a length equal to or shorter than the maximum length of the membrane, a width greater than 0.5mm, and a thickness 2 times greater than the thickness of the membrane except for the at least one thick portion.

28. The membrane of claim 27 wherein the thick portion protrudes from the two smooth surfaces and forms at least a portion of an edge of the membrane.

29. The membrane of claim 27 wherein the first thick portion forms at least a portion of a first edge of the membrane and the second thick portion forms at least a portion of a second edge of the membrane.

30. The membrane of claim 27 wherein the thick portion is effective to provide rigidity to the membrane.

31. The membrane of claim 27 further comprising a plurality of holes distributed along the thick portion.

32. The membrane of claim 25 wherein the membrane is non-porous and comprises polylactide.

33. A resorbable thin membrane comprising:

a first smooth surface and a second smooth surface, wherein the thickness between the first and second smooth surfaces is 0.01mm to 0.300 mm; and

at least one thick portion having a length equal to or shorter than a maximum length of the thin film, a width greater than 0.5mm, and a thickness 2 times greater than a thickness of the thin film at a portion other than the at least one thick portion, and having a viscosity characteristic equivalent to a pre-extrusion and pre-sterilization viscosity characteristic greater than 4 g/dL.

34. The membrane of claim 33 wherein the thick portion protrudes from the two smooth surfaces and forms at least a portion of an edge of the membrane.

35. The membrane of claim 33 comprising a first thick portion forming at least a portion of a first edge of the membrane and a second thick portion forming at least a portion of a second edge of the membrane.

36. The membrane of claim 33 further comprising a plurality of holes distributed along the thick portion.

37. The membrane of claim 33 wherein the at least one thick portion comprises a plurality of thick portions and the membrane is made of an amorphous polymer.

38. The membrane of claim 37 wherein the polymer comprises polylactide.

39. The membrane of claim 38 wherein the polymer comprises a copolymer of L-lactide and D, L-lactide.

40. The film of claim 37, wherein the polymer comprises caprolactone.

41. The film of claim 37 wherein the polymer has a biased molecular orientation toward one axis.

42. The film of claim 37 wherein the polymer has a biased molecular orientation towards two axes.

43. The membrane of claim 37 wherein the thickness between the first and second smooth surfaces is from 0.015mm to 0.025 mm.

44. The film of claim 37 wherein the film has a glass transition temperature and the thickness of the film increases by at least a factor of 5 upon heating the film to its glass transition temperature.

45. The film of claim 37 wherein the film has a glass transition temperature and the thickness of the film increases by at least a factor of 10 upon heating the film to its glass transition temperature.

46. The membrane of claim 37 wherein the membrane is liquid impermeable.

47. The film of claim 37, further comprising an additive impregnated in the film, the additive selected from one of the following groups: chemotactic substances for influencing cell migration, inhibitory substances for influencing cell migration, mitogenic growth factors for influencing cell proliferation and growth factors for influencing cell differentiation.

48. The film of claim 37 contained in sealed sterile packaging.

49. The membrane of claim 37 having a viscosity characteristic greater than 1 g/dL.

50. The membrane of claim 37 having a viscosity property greater than 2 g/dL.