Patent Grant
10363690
This application is a National Stage Application of PCT/EP13/066238 under 35 USC § 371 (a), which claims priority of French Patent Application Serial No. 12/57551 filed Aug. 2, 2012, the disclosures of each of the above-identified applications are hereby incorporated by reference in their entirety.
The present invention relates to a method for preparing a compressed porous layer of chitosan which has good mechanical strength, such a compressed porous layer being particularly useful for the manufacture of implants for reinforcing staple zones or lines, also called “buttresses”.
Staple line reinforcing implants are used in particular in gastrointestinal surgery for reinforcing the zones requiring a plurality of sutures or staples, for instance staple lines for reinforcing an intestinal anastomosis. These implants then serve to reinforce these zones in order to prevent or at least reduce possible bleeding and the potential subsequent complications. These reinforcing implants must have very good mechanical properties, in particular good resistance to suturing, in other words a high tensile strength before breaking.
Chitosan is a polysaccharide which results from the deacetylation of chitin. Chitin is one of the most widespread natural polysaccharides on earth and is extracted from the exoskeletons of arthropods, from the endoskeletons of cephalopods and also from fungi.
Chitosan has properties, such as biodegradability, bioresorbability, biocompatibility, non-toxicity and mechanical properties, which make it particularly advantageous for medical applications. Thus, chitosan can be incorporated into medical devices as a constituent of implants, for example in the form of sponges. Chitosan in fact offers a good compromise, given the desired properties, for a staple line reinforcing implant, namely good biological compatibility and good mechanical properties.
Moreover, staple line reinforcing implants, which may be permanent or biodegradable, must also have a good cell integration ability. Thus, these implants are often in the form of quite flat slabs formed from porous layers obtained from the lyophilization of a solution or solution of polymers.
Lyophilization involves a first step during which a solution is frozen in a particular structure, and then a second step, during which a controlled pressure is applied in order to cause sublimation of the water present in the frozen structure. At the end of the sublimation step, only the constituents present in the initial solution remain, thus producing a porous structure.
Once lyophilized, the chitosan-based porous layers are still very loaded with salts. These porous layers must therefore be neutralized and washed in order to remove these salts.
Moreover, the thickness of the implants for reinforcing staple zones or lines, or buttresses, is an important element of the effectiveness of the latter: indeed, this thickness must not be too great, so as, on the one hand, not to overload with foreign material the zones to be reinforced and, on the other hand, not to exceed the effectiveness-limiting height of the staples used; however, this thickness must not be too small either, so that the implant can perform its reinforcing role and the staple line can have a certain rigidity guaranteeing its durability, without damaging the biological tissue to be reinforced. Thus, the chitosan-based porous layers that it is desired to use as staple line reinforcements are generally compressed after lyophilization in order to attain a predetermined thickness. It is desirable to carry out this compression step before the neutralization step if it is desired for the deformation caused by the compression to be permanent and for the compressed layer not to reinflate in the presence of an aqueous medium such as biological fluids.
However, it has been observed that, when seeking to strongly compress chitosan-based porous layers, in particular when the chitosan concentration is high and the density of the resulting compressed layer is also high, the neutralization step is ineffective. In particular, such layers, although they have undergone a neutralization step, dissolve completely in the medium in which it is sought to wash them in order to eliminate any salts still remaining in these layers. These re-solubilizations result in the total destruction of the porous layer which can therefore no longer be used as a staple zone reinforcement.
It would be desirable to implement a method of preparing chitosan-based compressed porous layers that would avoid this phenomenon and would make it possible to effectively neutralize and wash such layers in order to prepare effective implants for reinforcing staple zones or lines, in particular buttresses.
The present invention relates to a method for preparing a chitosan-based porous layer which has been compressed, neutralized and washed, comprising the following steps:
The invention and the advantages thereof will emerge more clearly from the examples below and from the appended figures, in which:
The method according to the invention makes it possible to obtain chitosan-based porous layers which have been compressed, neutralized and washed, containing a high concentration of chitosan. The term “chitosan-based” is intended to mean according to the present application that the major compound of the porous layer is chitosan. In particular, the compressed, neutralized and washed porous layers of chitosan obtained by means of the method according to the invention have a particularly high density. Thus, the porous layers obtained by means of the method according to the invention have excellent tensile strength and excellent resistance to suturing. They therefore make it possible to obtain particularly effective implants for reinforcing staple zones or lines.
According to a first step of the method according to the invention, step a), a chitosan solution is prepared.
Chitosan is a biocompatible biopolymer resulting from the deacetylation of chitin. Chitin is extracted from exoskeletons of arthropods such as lobster, crab or shrimp, from the endoskeleton of cephalopods such as squid, or else from fungi. The extraction of chitin involves steps of protein and lipid hydrolysis, of depigmentation and of demineralization. Usually, the protein and lipid hydrolysis is carried out in the presence of sodium hydroxide, the demineralization requiring the use of hydrochloric acid.
Once the chitin has been extracted, the chitosan is obtained by means of a deacetylation step, which consists of hydrolysis of the acetamide groups. This reaction is generally carried out at high temperature in an alkaline solution, for example a solution of sodium hydroxide (NaOH) at 48% in water, at 90° C.
The following publications also describe methods for deacetylation of chitin in order to obtain chitosan: “Lamarque, G., C. Viton, and A. Domard, New Route of Deacetylation of α-and β-Chitins by Means of Freeze-Pump Out-Thaw Cycles. Biomacromolecules, 2005. 6(3): p. 1380-1388.”, “Lamarque, G., C. Viton, and A. Domard, Comparative Study of the First Heterogeneous Deacetylation of α-and β-Chitins in a Multistep Process. Biomacromolecules, 2004. 5(3): p. 992-1001.”, “Lamarque, G., C. Viton, and A. Domard, Comparative Study of the Second and Third Heterogeneous Deacetylations of α-and β-Chitins in a Multistep Process. Biomacromolecules, 2004. 5(5): p. 1899-1907.”, “Tolaimate, A., et al., Contribution to the preparation of chitins and chitosans with controlled physico-chemical properties. Polymer, 2003. 44(26): p. 7939-7952.”
Chitosans which are suitable as starting materials for the method according to the invention are available from the companies Kitozyme (fungus extract), Heppe Medical chitosan (shrimp or crab extract), Primex (shrimp extract) and Novamatrix (shrimp extract).
Chitosan is a biodegradable compound. The degree of acetylation of chitosan can have an influence on the chitosan degradation kinetics. Thus, depending on the biodegradation kinetics desired for the porous layer prepared according to the method of the invention, and therefore for the implant formed from this porous layer, the chitosan may have a degree of acetylation of 2, 3, 10, 20, 30, 40 or else 50%: the desired degree of acetylation can be obtained by preparing a mixture of several chitosans having various degrees of acetylation.
In one embodiment of the method according to the invention, the degree of acetylation of the chitosan ranges from 0 to 70%, preferably from 1% to 50%, preferably from 1% to 10% and more preferably from 2% to 3%. Such a chitosan makes it possible to obtain porous layers having optimum degradation kinetics and also a tissue growth substrate for the manufacture of staple line reinforcing implants.
The chitosan solution of step a) of the method according to the invention is generally prepared by solubilization of chitosan in powder form in water. The solution is adjusted to the desired pH, for example by adding acetic acid. In one embodiment of the method according to the invention, the pH of the chitosan solution is adjusted to a value ranging from 3 to 5, preferably to 3.5, for example by adding acetic acid. Such a pH makes it possible to obtain, in the end, a chitosan-based compressed porous layer which has good mechanical properties and which is capable of being stapled, for example.
In one embodiment of the method according to the invention, the solution of step a) is a solution of chitosan in water, the chitosan concentration in said solution ranging from 0.6% to 5%, preferably from 1% to 3% and more preferably from 2% to 3% by weight, relative to the total weight of the solution.
Such chitosan concentrations make it possible to obtain, in the end, compressed chitosan porous layers which have particularly good tensile strength and which are particularly resistant to suturing. Also preferably, the chitosan solution of the method according to the invention is free of any other polymer. The presence of a polymer other than chitosan in the solution could affect the lyophilization step and/or the compression step of the method according to the invention.
According to a second step of the method according to the invention, step b), the chitosan solution is poured into a mould in order to form a layer. Generally, the mould is in the shape of a rectangle having dimensions compatible with the use of the layer obtained as all or part of a reinforcing implant for staple zones in certain parts of the human body, for instance the gastrointestinal region.
According to a third step of the method according to the invention, step c), the layer obtained in b) is lyophilized so as to obtain a porous layer.
In the present application, the term “porous layer” is intended to mean a layer which has pores, or gaps, alveoli, holes, orifices, which are evenly or unevenly distributed not only at the surface, but also within the thickness of said layer, and which are more or less interconnected, depending on the lyophilization process used. Such lyophilization processes are known. It is known practice to vary the freezing temperature and speed and also the characteristics of the polymer solution to be lyophilized (pH, concentration, etc.), in this case chitosan, as a function of the structure of the sponge or porous layer that it is desired to obtain (see U.S. Pat. No. 4,970,298; Doillon et al, J Biomed Mater Res, 1986; Schoof, J Biomed Mater Res, 2001; O'Brien et al, Biomaterials, 2004).
According to a fourth step of the method according to the invention, step d), the porous layer obtained in c) is compressed. This compression can, for example, be carried out by means of a pneumatic press, such as a Mäder Pressen HP10000 HV10/50 press, Neuhausen, Germany.
The compression may be total, in other words it is carried out without inserting a wedge between the two jaws of the press used. In other embodiments of the method according to the invention, it is possible to insert a 2 mm wedge, or else a 1 mm wedge, in order to obtain a compressed layer respectively approximately 2 mm thick or 1 mm thick.
In one embodiment, the porous layer is compressed until a thickness of less than or equal to 2 mm, preferably less than or equal to 1 mm and more preferably less than or equal to 0.5 mm is obtained for said layer. This is because such thicknesses make it possible not to overload the staple zone that the reinforcing implant based on the porous layer obtained according to the invention will have to reinforce. In particular, this makes it possible not to exceed the load limiting height of the staples used and therefore to be able to use these staples effectively.
In particular, in one embodiment of the method according to the invention, said porous layer is compressed until a density of greater than or equal to 0.04 g/cm3, preferably greater than or equal to 0.19 g/cm3 and more preferably greater than or equal to 0.65 g/cm3 is obtained for said layer. Such densities make it possible to obtain, in the end, porous layers which have particularly good tensile strength and which are particularly resistant to suturing.
According to a fifth step of the method according to the invention, step e), the compressed porous chitosan layer obtained in d) is neutralized by means of an NH4OH solution.
In one embodiment of the method of the invention, the NH4OH solution is a solution of NH4OH in water or in ethanol, the NH4OH concentration in said solution ranging from 0.6 to 2 mol/l. For example, the NH4OH solution is a solution of NH4OH in ethanol, the NH4OH concentration in said solution ranging from 1 to 2 mol/l and preferably being 2 mol/l.
Such a solution allows effective neutralization of the compressed porous layers obtained in the previous step, both at the surface and at the heart of the layer, even if the layer has been strongly compressed, for example according to a total compression, and the layer has, after compression, a density greater than or equal to 0.20 g/cm3. After the compression step described above, the porous layer can have a very fine thickness, for example less than or equal to 2 mm, or else less than or equal to 1 mm, or else less than or equal to 0.5 mm: moreover, it can have a high chitosan concentration, for instance that obtained using a starting chitosan solution of 1% to 3% by weight, relative to the total weight of the solution. The neutralization by means of an NH4OH solution, in particular in water or in ethanol, the NH4OH concentration in said solution ranging from 0.6 to 2 mol/l, preferably in ethanol, the NH4OH concentration in said solution ranging from 1 to 2 mol/l and preferably being 2 mol/l, makes it possible to obtain deep neutralization of these high-density porous layers: in particular, the NH4OH solution penetrates to the heart of the compressed porous layer.
In one embodiment of the method of the invention, the compressed porous layer obtained in d) is neutralized by dipping into said NH4OH solution for a period of less than or equal to 30 min, preferably a period ranging from 5 min to 20 min. Such a period makes it possible to obtain a totally neutralized, compressed porous layer.
According to a sixth step of the method of the invention, step f), the neutralized compressed porous layer obtained in e) is subjected to one or more washing steps. The washing step makes it possible to eliminate from the porous layer any salts still remaining in this layer, for instance sodium acetate or ammonium acetate salts.
For example, the neutralized compressed porous layer is dipped in one or more baths of sterile water until a washing water with a pH close to 7 is obtained.
The porous chitosan layer which has been compressed, neutralized and washed according to the method of the invention can be part of or constitute the whole of an implant for reinforcing staple lines or zones. This is because these layers thus compressed, neutralized and washed have excellent tensile strength and excellent resistance to suturing.
Thus, another aspect of the invention relates to a chitosan-based porous layer which has been neutralized and washed, obtained from a layer obtained by lyophilization of a solution of chitosan in water, the chitosan concentration in said solution ranging from 0.6% to 5%, preferably from 1% to 3% and more preferably from 2% to 3% by weight, relative to the total weight of the solution, which layer has been compressed until a density of greater than or equal to 0.04 g/cm3, preferably greater than or equal to 0.19 g/cm3 and more preferably greater than or equal to 0.65 g/cm3 has been obtained for said compressed layer.
When the chitosan solution used in the method of the invention is free of any other polymer, the chitosan-based porous layer obtained is also free of any other polymer. In embodiments, the chitosan-based porous layer is free of any other polymer.
Porous chitosan layers which have been compressed and neutralized are prepared according to the following protocols:
1°) Preparation of Chitosan Solutions at Different Chitosan Concentrations, and Having Different Weights:
15 g of chitosan with a 2% degree of acetylation (DA) was solubilized in 1344 ml of sterile water by adding 5.5 ml of acetic acid with stirring. The solution was brought from a pH of 5.11 to a pH of 3.5 by adding 39 ml of acetic acid. The solution was then diluted by adding 92 ml of sterile water in order to obtain a chitosan solution at 1% by weight, relative to the total weight of the solution (called 1% solution).
A part of this solution was used to prepare solution samples weighing, respectively, 60 g, 80 g and 100 g.
Another part of this 1% solution, namely 958.5 g, was diluted by adding 240 ml of sterile water and was adjusted to pH 3.5 by adding 0.5 ml of acetic acid. A solution of chitosan at 0.8% by weight, relative to the total weight of the solution (called 0.8% solution), is obtained. A part of this 0.8% solution is used to prepare solution samples weighing, respectively, 60 g, 80 g and 100 g.
Another part of the 0.8% solution, namely 680 g, is diluted by adding 227 ml of sterile water and is adjusted to pH 3.5 by adding 0.5 ml of acetic acid. A chitosan solution at 0.6% by weight, relative to the total weight of the solution (called 0.6% solution), is obtained. This 0.6% solution is used to prepare solution samples weighting, respectively, 60 g, 80 g and 100 g.
The various types of samples of solutions S1-S9 collated in Table I below are therefore obtained:
1%
1%
1%
2°) Preparation of Compressed Porous Layers from the Solutions Obtained in 1°):
After centrifugation, all the samples of solutions prepared in 1°) were each poured into a rectangular mould with dimensions 12 cm×17 cm, and then lyophilized for 28 h.
The porous layers C1-C9 obtained, respectively, from the lyophilization of the solutions S1-S9 of point 1°) are thus obtained.
The porous layers C1-C9 are then each subjected to a compression according to the following protocol: each layer is compressed using a pneumatic press (Mäder Pressen HP10000 HV10/50, Neuhausen, Germany) fixed at 4 bar for a cycle of 13 seconds. A final load of 67 kN is applied during the cycle after 4 seconds and is maintained until the end of the cycle. This compression is carried out without wedges.
The compressed porous layers CC1-CC9, obtained, respectively, from the porous layers C1-C9 above, are thus obtained, said compressed porous layers having the following characteristics:
3°) Preparation of Compressed Porous Layers Neutralized with Ammonia (According to the Invention):
A part of the compressed porous layers CC1-CC9 obtained in 2°) are subjected to a neutralization step according to the following protocol: each layer is dipped in a solution of NH4OH at 1 mol/l in ethanol for 5 min for the purpose of eliminating the salts potentially remaining in the layer.
It is noted that the layers are effectively neutralized. They can then be washed in baths of sterile water, until a washing water with a pH close to 7 is obtained, without risk of re-solubilization.
These porous chitosan layers which have been compressed, neutralized and washed can be used effectively in staple line reinforcing implants. They have tensile strength and are resistant to suturing.)
4°) Preparation of Compressed Porous Layers Neutralized with Sodium Hydroxide (Comparative):
The other part of the compressed porous layers CC1-CC9 obtained in 2°) is subjected to a neutralization step according to the following protocol: each layer is dipped in a solution of NaOH at 0.5 mol/l in ethanol for 5 min, for the purpose of eliminating the salts potentially remaining in the layer.
It is noted that only the surface of the layer is neutralized. During the washes in the baths of sterile water which follow the neutralization step, it is noted that the compressed porous layer re-solubilizes and is therefore destroyed.
Thus, it is not possible to obtain porous layers which have been compressed, neutralized and washed, when the neutralization is carried out with sodium hydroxide.
Porous chitosan layers were prepared according to the following protocols:
1°) Preparation of Compressed Porous Chitosan Layers:
21 g of chitosan with a 3% degree of acetylation (DA) were solubilized in 2442 ml of sterile water by adding 8 ml of acetic acid with stirring. The solution was brought from a pH of 5.11 to a pH of 3.5 by adding 60 ml of acetic acid. The solution was then diluted by adding 94 ml of sterile water in order to obtain a chitosan solution at 0.8% by weight, relative to the total weight of the solution.
Samples of this solution were centrifuged and then each poured into a rectangular mould with dimensions of 12 cm×17 cm, and then lyophilized for 28 h.
The porous layers obtained by lyophilization were then compressed in the same way as in EXAMPLE 1.)
2°) Neutralization of the Compressed Porous Layers Obtained in 1°):
Six compressed porous layers obtained in 1°), namely the samples CC11-CC16, were neutralized, each according to a different protocol, detailed hereinafter:
The compressed porous layers CC11-CC16 neutralized as described above were then washed twice in sterile water. Their quality was then evaluated visually in the following way:
The results are collated in Table III below:
A chitosan solution at 2% by weight, relative to the total weight of the solution, and having a pH of 3.5, was prepared.
Samples of 121 g of this solution were centrifuged and then each poured into a rectangular mould with dimensions of 12 cm×17 cm, and then lyophilized for 28 h.
The porous layers obtained by lyophilization were then compressed in the same way as in EXAMPLE 1.
A part of the compressed porous chitosan layers thus obtained were neutralized by dipping in an NH4OH solution at 1 mol/l for 20 min: the neutralization was effective.
Another part of the compressed porous chitosan layers thus obtained was neutralized by dipping in a solution of NH4OH at 2 mol/l in ethanol for 5 min: the neutralization was effective.
According to the preparation method of EXAMPLE 1, chitosan solutions at pH 3.5 were prepared at respective concentrations of 1%, 2% and 3%, by weight, relative to the total weight of the solution. 121 g solution samples were then prepared. After centrifugation, these solution samples were each poured into a rectangular mould with dimensions of 12 cm×17 cm, and then lyophilized for 28 h.
Porous chitosan layers were thus obtained. For each initial chitosan concentration, samples of these porous layers were compressed, each according to one of the following three protocols:
Total Compression:
The layer is compressed using a pneumatic press (Mäder Pressen HP10000 HV10/50, Neuhausen, Germany) fixed at 6 bar for a cycle of 13 seconds. This compression is carried out without wedges.
2 mm Compression:
Corresponds to the protocol above for total compression, but a 2 mm wedge is inserted between the two jaws of the press.
1 mm Compression:
Corresponds to the protocol above for total compression, but a 1 mm wedge is inserted between the two jaws of the press.
The samples of compressed porous layers and the values of their respective density after compression are collated in Table IV below, in which:
All the compressed porous layers obtained were neutralized by dipping in a solution of NH4OH at 2 mol/l in ethanol for 20 min: the neutralization was effective.
The neutralized layers were then washed in baths of sterile water until washing water with a pH close to 7 was obtained. No re-solubilization of the layers was noted during this washing step.
Thus, the method according to the invention makes it possible to neutralize and wash porous chitosan layers having particularly high densities, which can range up to 0.75 g/cm3, for example having densities greater than or equal to 0.65 g/cm3 (see CC21, CC27 and CC24). The method according to the invention also makes it possible to neutralize and wash porous chitosan layers of which the chitosan concentration is particularly high, in particular porous chitosan layers obtained from a starting solution containing 3% chitosan (see CC27-29).
Moreover, the final density (FD) of the above compressed porous layers after neutralization was calculated according to the following formula: W×C/VF, where W is the weight of the layer, C is the chitosan concentration by weight, relative to the total weight of the starting solution, and VF is the volume of the layer measured after neutralization. The results are set out in Table V below:
Tensile Strength Tests:
The tensile strength of the above compressed porous layers which have been neutralized and washed, CC21-29, was evaluated according to the following protocol: with reference to
The results are collated in Table VI below, in which the value of the force F corresponds to the mean for five tests.
These results show that the tensile strength of the porous chitosan layers obtained according to the method of the invention is particularly high. These porous layers are thus entirely useful for the manufacture of implants for reinforcing staple zones or lines.
Tests for Resistance to Suturing:
The resistance to suturing of the above compressed porous layers which have been neutralized and washed, CC21-29, was evaluated according to the following protocol: with reference to
The results are collated in Table VII below, in which the value of the force F corresponds to the mean for five tests.
These results show that the resistance to suturing of the porous chitosan layers obtained according to the method of the invention is particularly high. These porous layers are thus entirely useful for the manufacture of implants for reinforcing staple zones or lines.
| Number | Date | Country | Kind |
|---|---|---|---|
| 12 57551 | Aug 2012 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2013/066238 | 8/1/2013 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2014/020132 | 2/6/2014 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 1187158 | Mcginley | Jun 1916 | A |
| 3054406 | Usher | Sep 1962 | A |
| 3118294 | Van Laethem | Jan 1964 | A |
| 3124136 | Usher | Mar 1964 | A |
| 3272204 | Charles et al. | Sep 1966 | A |
| 3276448 | Usher | Oct 1966 | A |
| 3320649 | Naimer | May 1967 | A |
| 3364200 | Ashton et al. | Jan 1968 | A |
| 3570482 | Emoto et al. | Mar 1971 | A |
| 3718725 | Hamano | Feb 1973 | A |
| 4006747 | Kronenthal et al. | Feb 1977 | A |
| 4060081 | Yannas et al. | Nov 1977 | A |
| 4173131 | Pendergrass et al. | Nov 1979 | A |
| 4193137 | Heck | Mar 1980 | A |
| 4248064 | Odham | Feb 1981 | A |
| 4294241 | Miyata | Oct 1981 | A |
| 4307717 | Hymes et al. | Dec 1981 | A |
| 4338800 | Matsuda | Jul 1982 | A |
| 4476697 | Schafer et al. | Oct 1984 | A |
| 4487865 | Balazs et al. | Dec 1984 | A |
| 4500676 | Balazs et al. | Feb 1985 | A |
| 4511653 | Play et al. | Apr 1985 | A |
| 4527404 | Nakagaki et al. | Jul 1985 | A |
| 4591501 | Cioca | May 1986 | A |
| 4597762 | Walter et al. | Jul 1986 | A |
| 4603695 | Ikada et al. | Aug 1986 | A |
| 4631932 | Sommers | Dec 1986 | A |
| 4670014 | Huc et al. | Jun 1987 | A |
| 4709562 | Matsuda | Dec 1987 | A |
| 4748078 | Doi et al. | May 1988 | A |
| 4759354 | Quarfoot | Jul 1988 | A |
| 4769038 | Bendavid et al. | Sep 1988 | A |
| 4796603 | Dahlke et al. | Jan 1989 | A |
| 4813942 | Alvarez | Mar 1989 | A |
| 4841962 | Berg et al. | Jun 1989 | A |
| 4854316 | Davis | Aug 1989 | A |
| 4925294 | Geshwind et al. | May 1990 | A |
| 4931546 | Tardy et al. | Jun 1990 | A |
| 4942875 | Hlavacek et al. | Jul 1990 | A |
| 4948540 | Nigam | Aug 1990 | A |
| 4950483 | Ksander et al. | Aug 1990 | A |
| 4970298 | Silver et al. | Nov 1990 | A |
| 4976737 | Leake | Dec 1990 | A |
| 5002551 | Linsky et al. | Mar 1991 | A |
| 5015584 | Brysk | May 1991 | A |
| 5116357 | Eberbach | May 1992 | A |
| 5147374 | Fernandez | Sep 1992 | A |
| 5162430 | Rhee et al. | Nov 1992 | A |
| 5171273 | Silver et al. | Dec 1992 | A |
| 5176692 | Wilk et al. | Jan 1993 | A |
| 5192301 | Kamiya et al. | Mar 1993 | A |
| 5195542 | Gazielly et al. | Mar 1993 | A |
| 5196185 | Silver et al. | Mar 1993 | A |
| 5201745 | Tayot et al. | Apr 1993 | A |
| 5201764 | Kelman et al. | Apr 1993 | A |
| 5206028 | Li | Apr 1993 | A |
| 5217493 | Raad et al. | Jun 1993 | A |
| 5254133 | Seid | Oct 1993 | A |
| 5256418 | Kemp et al. | Oct 1993 | A |
| 5258000 | Gianturco | Nov 1993 | A |
| 5263983 | Yoshizato et al. | Nov 1993 | A |
| 5304595 | Rhee et al. | Apr 1994 | A |
| 5306500 | Rhee et al. | Apr 1994 | A |
| 5324775 | Rhee et al. | Jun 1994 | A |
| 5328955 | Rhee et al. | Jul 1994 | A |
| 5334527 | Brysk | Aug 1994 | A |
| 5339657 | McMurray | Aug 1994 | A |
| 5350583 | Yoshizato et al. | Sep 1994 | A |
| 5356432 | Rutkow et al. | Oct 1994 | A |
| 5368549 | McVicker | Nov 1994 | A |
| 5368602 | de la Torre | Nov 1994 | A |
| 5370650 | Tovey et al. | Dec 1994 | A |
| 5376375 | Rhee et al. | Dec 1994 | A |
| 5376376 | Li | Dec 1994 | A |
| 5397331 | Himpens et al. | Mar 1995 | A |
| 5399361 | Song et al. | Mar 1995 | A |
| 5413791 | Rhee et al. | May 1995 | A |
| 5425740 | Hutchinson, Jr. | Jun 1995 | A |
| 5428022 | Palefsky et al. | Jun 1995 | A |
| 5433996 | Kranzler et al. | Jul 1995 | A |
| 5441491 | Verschoor et al. | Aug 1995 | A |
| 5441508 | Gazielly et al. | Aug 1995 | A |
| 5456693 | Conston et al. | Oct 1995 | A |
| 5456711 | Hudson | Oct 1995 | A |
| 5466462 | Rosenthal et al. | Nov 1995 | A |
| 5480644 | Freed | Jan 1996 | A |
| 5487895 | Dapper et al. | Jan 1996 | A |
| 5490984 | Freed | Feb 1996 | A |
| 5512291 | Li | Apr 1996 | A |
| 5512301 | Song et al. | Apr 1996 | A |
| 5514181 | Light et al. | May 1996 | A |
| 5522840 | Krajicek | Jun 1996 | A |
| 5523348 | Rhee et al. | Jun 1996 | A |
| 5525710 | Unger | Jun 1996 | A |
| 5536656 | Kemp et al. | Jul 1996 | A |
| 5543441 | Rhee et al. | Aug 1996 | A |
| 5565210 | Rosenthal et al. | Oct 1996 | A |
| 5567806 | Abdul-Malak et al. | Oct 1996 | A |
| 5569273 | Titone et al. | Oct 1996 | A |
| RE35399 | Eisenberg | Dec 1996 | E |
| 5593441 | Lichtenstein et al. | Jan 1997 | A |
| 5595621 | Light et al. | Jan 1997 | A |
| 5601571 | Moss | Feb 1997 | A |
| 5607474 | Athanasiou et al. | Mar 1997 | A |
| 5607590 | Shimizu | Mar 1997 | A |
| 5614587 | Rhee et al. | Mar 1997 | A |
| 5618551 | Tardy et al. | Apr 1997 | A |
| 5634931 | Kugel | Jun 1997 | A |
| 5639796 | Lee | Jun 1997 | A |
| 5665391 | Lea | Sep 1997 | A |
| 5667839 | Berg | Sep 1997 | A |
| 5676967 | Williams et al. | Oct 1997 | A |
| 5681568 | Goldin et al. | Oct 1997 | A |
| 5686090 | Schilder et al. | Nov 1997 | A |
| 5686115 | Vournakis et al. | Nov 1997 | A |
| 5690675 | Sawyer et al. | Nov 1997 | A |
| 5695525 | Mulhauser et al. | Dec 1997 | A |
| 5697978 | Sgro | Dec 1997 | A |
| 5700476 | Rosenthal et al. | Dec 1997 | A |
| 5700477 | Rosenthal et al. | Dec 1997 | A |
| 5702416 | Kieturakis et al. | Dec 1997 | A |
| 5709934 | Bell et al. | Jan 1998 | A |
| 5711960 | Shikinami | Jan 1998 | A |
| 5716409 | Debbas | Feb 1998 | A |
| 5720981 | Eisinger | Feb 1998 | A |
| 5732572 | Litton | Mar 1998 | A |
| 5743917 | Saxon | Apr 1998 | A |
| 5749895 | Sawyer et al. | May 1998 | A |
| 5752974 | Rhee et al. | May 1998 | A |
| 5766246 | Mulhauser et al. | Jun 1998 | A |
| 5766631 | Arnold | Jun 1998 | A |
| 5769864 | Kugel | Jun 1998 | A |
| 5771716 | Schlussel | Jun 1998 | A |
| 5785983 | Furlan et al. | Jul 1998 | A |
| 5800541 | Rhee et al. | Sep 1998 | A |
| 5814328 | Gunasekaran | Sep 1998 | A |
| 5833705 | Ken et al. | Nov 1998 | A |
| 5840011 | Landgrebe et al. | Nov 1998 | A |
| 5861034 | Taira et al. | Jan 1999 | A |
| 5863984 | Doillon et al. | Jan 1999 | A |
| 5869080 | McGregor et al. | Feb 1999 | A |
| 5871767 | Dionne et al. | Feb 1999 | A |
| 5876444 | Lai | Mar 1999 | A |
| 5891558 | Bell et al. | Apr 1999 | A |
| 5899909 | Claren et al. | May 1999 | A |
| 5906937 | Sugiyama et al. | May 1999 | A |
| 5910149 | Kuzmak | Jun 1999 | A |
| 5911731 | Pham et al. | Jun 1999 | A |
| 5916225 | Kugel | Jun 1999 | A |
| 5919232 | Chaffringeon et al. | Jul 1999 | A |
| 5919233 | Knopf et al. | Jul 1999 | A |
| 5922026 | Chin | Jul 1999 | A |
| 5931165 | Reich et al. | Aug 1999 | A |
| 5942278 | Hagedorn et al. | Aug 1999 | A |
| 5962136 | Dewez et al. | Oct 1999 | A |
| 5972022 | Huxel | Oct 1999 | A |
| RE36370 | Li | Nov 1999 | E |
| 5993844 | Abraham et al. | Nov 1999 | A |
| 5994325 | Roufa et al. | Nov 1999 | A |
| 5997895 | Narotam et al. | Dec 1999 | A |
| 6001895 | Harvey et al. | Dec 1999 | A |
| 6008292 | Lee et al. | Dec 1999 | A |
| 6015844 | Harvey et al. | Jan 2000 | A |
| 6039686 | Kovac | Mar 2000 | A |
| 6042534 | Gellman et al. | Mar 2000 | A |
| 6042592 | Schmitt | Mar 2000 | A |
| 6043089 | Sugiyama et al. | Mar 2000 | A |
| 6051425 | Morota et al. | Apr 2000 | A |
| 6056688 | Benderev et al. | May 2000 | A |
| 6056970 | Greenawalt et al. | May 2000 | A |
| 6057148 | Sugiyama et al. | May 2000 | A |
| 6063396 | Kelleher | May 2000 | A |
| 6066776 | Goodwin et al. | May 2000 | A |
| 6066777 | Benchetrit | May 2000 | A |
| 6071292 | Makower et al. | Jun 2000 | A |
| 6077281 | Das | Jun 2000 | A |
| 6080194 | Pachence et al. | Jun 2000 | A |
| 6083522 | Chu et al. | Jul 2000 | A |
| 6090116 | D'Aversa et al. | Jul 2000 | A |
| 6113623 | Sgro | Sep 2000 | A |
| 6120539 | Eldridge et al. | Sep 2000 | A |
| 6132765 | DiCosmo et al. | Oct 2000 | A |
| 6143037 | Goldstein et al. | Nov 2000 | A |
| 6153292 | Bell et al. | Nov 2000 | A |
| 6162962 | Hinsch et al. | Dec 2000 | A |
| 6165488 | Tardy et al. | Dec 2000 | A |
| 6171318 | Kugel et al. | Jan 2001 | B1 |
| 6174320 | Kugel et al. | Jan 2001 | B1 |
| 6176863 | Kugel et al. | Jan 2001 | B1 |
| 6179872 | Bell et al. | Jan 2001 | B1 |
| 6180848 | Flament et al. | Jan 2001 | B1 |
| 6197325 | MacPhee et al. | Mar 2001 | B1 |
| 6197934 | DeVore et al. | Mar 2001 | B1 |
| 6197935 | Doillon et al. | Mar 2001 | B1 |
| 6210439 | Firmin et al. | Apr 2001 | B1 |
| 6214020 | Mulhauser et al. | Apr 2001 | B1 |
| 6221109 | Geistlich et al. | Apr 2001 | B1 |
| 6224616 | Kugel | May 2001 | B1 |
| 6241768 | Agarwal et al. | Jun 2001 | B1 |
| 6258124 | Darois et al. | Jul 2001 | B1 |
| 6262332 | Ketharanathan | Jul 2001 | B1 |
| 6264702 | Ory et al. | Jul 2001 | B1 |
| 6267772 | Mulhauser et al. | Jul 2001 | B1 |
| 6270530 | Eldridge et al. | Aug 2001 | B1 |
| 6277397 | Shimizu | Aug 2001 | B1 |
| 6280453 | Kugel et al. | Aug 2001 | B1 |
| 6287316 | Agarwal et al. | Sep 2001 | B1 |
| 6290708 | Kugel et al. | Sep 2001 | B1 |
| 6306079 | Trabucco | Oct 2001 | B1 |
| 6306424 | Vyakarnam et al. | Oct 2001 | B1 |
| 6312474 | Francis et al. | Nov 2001 | B1 |
| 6319264 | Tormala et al. | Nov 2001 | B1 |
| 6328686 | Kovac | Dec 2001 | B1 |
| 6334872 | Termin et al. | Jan 2002 | B1 |
| 6383201 | Dong | May 2002 | B1 |
| 6391060 | Ory et al. | May 2002 | B1 |
| 6391333 | Li et al. | May 2002 | B1 |
| 6391939 | Tayot et al. | May 2002 | B2 |
| 6408656 | Ory et al. | Jun 2002 | B1 |
| 6410044 | Chudzik et al. | Jun 2002 | B1 |
| 6413742 | Olsen et al. | Jul 2002 | B1 |
| 6425924 | Rousseau | Jul 2002 | B1 |
| 6428978 | Olsen et al. | Aug 2002 | B1 |
| 6436030 | Rehil | Aug 2002 | B2 |
| 6440167 | Shimizu | Aug 2002 | B2 |
| 6443964 | Ory et al. | Sep 2002 | B1 |
| 6447551 | Goldmann | Sep 2002 | B1 |
| 6447802 | Sessions et al. | Sep 2002 | B2 |
| 6448378 | DeVore et al. | Sep 2002 | B2 |
| 6451032 | Ory et al. | Sep 2002 | B1 |
| 6451301 | Sessions et al. | Sep 2002 | B1 |
| 6454787 | Maddalo et al. | Sep 2002 | B1 |
| 6477865 | Matsumoto | Nov 2002 | B1 |
| 6479072 | Morgan et al. | Nov 2002 | B1 |
| 6485503 | Jacobs et al. | Nov 2002 | B2 |
| 6500464 | Ceres et al. | Dec 2002 | B2 |
| 6500777 | Wiseman et al. | Dec 2002 | B1 |
| 6509031 | Miller et al. | Jan 2003 | B1 |
| 6511958 | Atkinson et al. | Jan 2003 | B1 |
| 6514286 | Leatherbury et al. | Feb 2003 | B1 |
| 6514514 | Atkinson et al. | Feb 2003 | B1 |
| 6540773 | Dong | Apr 2003 | B2 |
| 6541023 | Andre et al. | Apr 2003 | B1 |
| 6548077 | Gunasekaran | Apr 2003 | B1 |
| 6554855 | Dong | Apr 2003 | B1 |
| 6559119 | Burgess et al. | May 2003 | B1 |
| 6566345 | Miller et al. | May 2003 | B2 |
| 6575988 | Rousseau | Jun 2003 | B2 |
| 6576019 | Atala | Jun 2003 | B1 |
| 6596002 | Therin et al. | Jul 2003 | B2 |
| 6596304 | Bayon et al. | Jul 2003 | B1 |
| 6599323 | Melican et al. | Jul 2003 | B2 |
| 6599524 | Li et al. | Jul 2003 | B2 |
| 6599690 | Abraham et al. | Jul 2003 | B1 |
| 6610006 | Amid et al. | Aug 2003 | B1 |
| 6613348 | Jain | Sep 2003 | B1 |
| 6616685 | Rousseau | Sep 2003 | B2 |
| 6623963 | Muller et al. | Sep 2003 | B1 |
| 6630414 | Matsumoto | Oct 2003 | B1 |
| 6637437 | Hungerford et al. | Oct 2003 | B1 |
| 6638284 | Rousseau et al. | Oct 2003 | B1 |
| 6645226 | Jacobs et al. | Nov 2003 | B1 |
| 6652594 | Francis et al. | Nov 2003 | B2 |
| 6652595 | Nicolo | Nov 2003 | B1 |
| 6653450 | Berg et al. | Nov 2003 | B1 |
| 6656206 | Corcoran et al. | Dec 2003 | B2 |
| 6660280 | Allard et al. | Dec 2003 | B1 |
| 6669735 | Pelissier | Dec 2003 | B1 |
| 6670018 | Fujita et al. | Dec 2003 | B2 |
| 6682760 | Noff et al. | Jan 2004 | B2 |
| 6685714 | Rousseau | Feb 2004 | B2 |
| 6706684 | Bayon et al. | Mar 2004 | B1 |
| 6706690 | Reich et al. | Mar 2004 | B2 |
| 6712859 | Rousseau et al. | Mar 2004 | B2 |
| 6719795 | Cornwall et al. | Apr 2004 | B1 |
| 6723335 | Moehlenbruck et al. | Apr 2004 | B1 |
| 6726660 | Hessel et al. | Apr 2004 | B2 |
| 6730299 | Tayot et al. | May 2004 | B1 |
| 6736823 | Darois et al. | May 2004 | B2 |
| 6736854 | Vadurro et al. | May 2004 | B2 |
| 6737371 | Planck et al. | May 2004 | B1 |
| 6743435 | DeVore et al. | Jun 2004 | B2 |
| 6746458 | Cloud | Jun 2004 | B1 |
| 6752834 | Geistlich et al. | Jun 2004 | B2 |
| 6755868 | Rousseau | Jun 2004 | B2 |
| 6773723 | Spiro et al. | Aug 2004 | B1 |
| 6783554 | Amara et al. | Aug 2004 | B2 |
| 6790213 | Cherok et al. | Sep 2004 | B2 |
| 6790454 | Abdul Malak et al. | Sep 2004 | B1 |
| 6800082 | Rousseau | Oct 2004 | B2 |
| 6833408 | Sehl et al. | Dec 2004 | B2 |
| 6835336 | Watt | Dec 2004 | B2 |
| 6852330 | Bowman et al. | Feb 2005 | B2 |
| 6869938 | Schwartz et al. | Mar 2005 | B1 |
| 6872227 | Sump et al. | Mar 2005 | B2 |
| 6893653 | Abraham et al. | May 2005 | B2 |
| 6896904 | Spiro et al. | May 2005 | B2 |
| 6926723 | Mulhauser et al. | Aug 2005 | B1 |
| 6936276 | Spiro et al. | Aug 2005 | B2 |
| 6939562 | Spiro et al. | Sep 2005 | B2 |
| 6949625 | Tayot | Sep 2005 | B2 |
| 6966918 | Schuldt-Hempe et al. | Nov 2005 | B1 |
| 6971252 | Therin et al. | Dec 2005 | B2 |
| 6974679 | Andre et al. | Dec 2005 | B2 |
| 6974862 | Ringeisen et al. | Dec 2005 | B2 |
| 6977231 | Matsuda | Dec 2005 | B1 |
| 6984392 | Bechert et al. | Jan 2006 | B2 |
| 6988386 | Okawa et al. | Jan 2006 | B1 |
| 7011688 | Gryska et al. | Mar 2006 | B2 |
| 7021086 | Ory et al. | Apr 2006 | B2 |
| 7022358 | Eckmayer et al. | Apr 2006 | B2 |
| 7025063 | Snitkin et al. | Apr 2006 | B2 |
| 7041868 | Greene et al. | May 2006 | B2 |
| 7060103 | Carr, Jr. et al. | Jun 2006 | B2 |
| RE39172 | Bayon et al. | Jul 2006 | E |
| 7070558 | Gellman et al. | Jul 2006 | B2 |
| 7087065 | Ulmsten et al. | Aug 2006 | B2 |
| 7094261 | Zotti et al. | Aug 2006 | B2 |
| 7098315 | Schaufler | Aug 2006 | B2 |
| 7101381 | Ford et al. | Sep 2006 | B2 |
| 7115220 | Dubson et al. | Oct 2006 | B2 |
| 7156804 | Nicolo | Jan 2007 | B2 |
| 7156858 | Schuldt-Hempe et al. | Jan 2007 | B2 |
| 7175852 | Simmoteit et al. | Feb 2007 | B2 |
| 7192604 | Brown et al. | Mar 2007 | B2 |
| 7207962 | Anand et al. | Apr 2007 | B2 |
| 7214765 | Ringeisen et al. | May 2007 | B2 |
| 7226611 | Yura et al. | Jun 2007 | B2 |
| 7229453 | Anderson et al. | Jun 2007 | B2 |
| 7252837 | Guo et al. | Aug 2007 | B2 |
| 7279177 | Looney et al. | Oct 2007 | B2 |
| 7331199 | Ory et al. | Feb 2008 | B2 |
| 7393319 | Merade et al. | Jul 2008 | B2 |
| 7556598 | Rao | Jul 2009 | B2 |
| 7594921 | Browning | Sep 2009 | B2 |
| 7614258 | Cherok et al. | Nov 2009 | B2 |
| 7615065 | Priewe et al. | Nov 2009 | B2 |
| 7662169 | Wittmann | Feb 2010 | B2 |
| 7670380 | Cauthen, III | Mar 2010 | B2 |
| 7682381 | Rakos et al. | Mar 2010 | B2 |
| 7709017 | Tayot | May 2010 | B2 |
| 7718556 | Matsuda et al. | May 2010 | B2 |
| 7732354 | Fricke et al. | Jun 2010 | B2 |
| 7785334 | Ford et al. | Aug 2010 | B2 |
| 7789888 | Bartee et al. | Sep 2010 | B2 |
| 7799767 | Lamberti et al. | Sep 2010 | B2 |
| 7806905 | Ford et al. | Oct 2010 | B2 |
| 7824420 | Eldridge et al. | Nov 2010 | B2 |
| 7828854 | Rousseau et al. | Nov 2010 | B2 |
| 7900484 | Cherok et al. | Mar 2011 | B2 |
| 7931695 | Ringeisen | Apr 2011 | B2 |
| 8052759 | Dupic et al. | Nov 2011 | B2 |
| 8079023 | Chen | Dec 2011 | B2 |
| 8100924 | Browning | Jan 2012 | B2 |
| 8123817 | Intoccia et al. | Feb 2012 | B2 |
| 8142515 | Therin et al. | Mar 2012 | B2 |
| 8157821 | Browning | Apr 2012 | B2 |
| 8157822 | Browning | Apr 2012 | B2 |
| 8182545 | Cherok et al. | May 2012 | B2 |
| 8197837 | Jamiolkowski et al. | Jun 2012 | B2 |
| 8206632 | Rousseau et al. | Jun 2012 | B2 |
| 8215310 | Browning | Jul 2012 | B2 |
| 8317872 | Adams | Nov 2012 | B2 |
| 8323675 | Greenawalt | Dec 2012 | B2 |
| 8343232 | Adzich et al. | Jan 2013 | B2 |
| 8366787 | Brown et al. | Feb 2013 | B2 |
| 8435307 | Paul | May 2013 | B2 |
| 8470355 | Skalla et al. | Jun 2013 | B2 |
| 8562633 | Cully et al. | Oct 2013 | B2 |
| 8574627 | Martakos et al. | Nov 2013 | B2 |
| 8709094 | Stad et al. | Apr 2014 | B2 |
| 8734471 | Deitch | May 2014 | B2 |
| 8753360 | Gleiman et al. | Jun 2014 | B2 |
| 8758800 | Stopek et al. | Jun 2014 | B2 |
| 8784294 | Goddard | Jul 2014 | B2 |
| 8814887 | Walther et al. | Aug 2014 | B2 |
| 8828092 | Toso et al. | Sep 2014 | B2 |
| 8834864 | Odar et al. | Sep 2014 | B2 |
| 8846060 | Archibald et al. | Sep 2014 | B2 |
| 8865215 | Ladet et al. | Oct 2014 | B2 |
| 8877233 | Obermiller et al. | Nov 2014 | B2 |
| 8911504 | Mathisen et al. | Dec 2014 | B2 |
| 8920370 | Sholev et al. | Dec 2014 | B2 |
| 8956373 | Ford et al. | Feb 2015 | B2 |
| 8962006 | Bayon et al. | Feb 2015 | B2 |
| 8968762 | Ladet et al. | Mar 2015 | B2 |
| 8979935 | Lozier et al. | Mar 2015 | B2 |
| 9034357 | Stopek | May 2015 | B2 |
| 9113993 | Lee | Aug 2015 | B2 |
| 9211175 | Stopek et al. | Dec 2015 | B2 |
| 9216075 | Bailly et al. | Dec 2015 | B2 |
| 20020087174 | Capello | Jul 2002 | A1 |
| 20020095218 | Carr et al. | Jul 2002 | A1 |
| 20030086975 | Ringeisen | May 2003 | A1 |
| 20030114937 | Leatherbury et al. | Jun 2003 | A1 |
| 20030133967 | Ruszczak et al. | Jul 2003 | A1 |
| 20030190346 | Lee | Oct 2003 | A1 |
| 20030225355 | Butler | Dec 2003 | A1 |
| 20040034373 | Schuldt-Hempe et al. | Feb 2004 | A1 |
| 20040054376 | Ory et al. | Mar 2004 | A1 |
| 20040059356 | Gingras | Mar 2004 | A1 |
| 20040101546 | Gorman et al. | May 2004 | A1 |
| 20050002893 | Goldmann | Jan 2005 | A1 |
| 20050021058 | Negro | Jan 2005 | A1 |
| 20050085924 | Darois et al. | Apr 2005 | A1 |
| 20050113849 | Popadiuk et al. | May 2005 | A1 |
| 20050137512 | Campbell et al. | Jun 2005 | A1 |
| 20050142161 | Freeman et al. | Jun 2005 | A1 |
| 20050148963 | Brennan | Jul 2005 | A1 |
| 20050175659 | Macomber et al. | Aug 2005 | A1 |
| 20050232979 | Shoshan | Oct 2005 | A1 |
| 20050267521 | Forsberg | Dec 2005 | A1 |
| 20050288691 | Leiboff | Dec 2005 | A1 |
| 20060116696 | Odermatt et al. | Jun 2006 | A1 |
| 20060135921 | Wiercinski et al. | Jun 2006 | A1 |
| 20060147501 | Hillas et al. | Jul 2006 | A1 |
| 20060216320 | Kitazono et al. | Sep 2006 | A1 |
| 20060252981 | Matsuda et al. | Nov 2006 | A1 |
| 20060253203 | Alvarado | Nov 2006 | A1 |
| 20060282103 | Fricke et al. | Dec 2006 | A1 |
| 20070021703 | McCarthy | Jan 2007 | A1 |
| 20070088391 | McAlexander et al. | Apr 2007 | A1 |
| 20070129736 | Solecki | Jun 2007 | A1 |
| 20070198040 | Buevich et al. | Aug 2007 | A1 |
| 20070299538 | Roeber | Dec 2007 | A1 |
| 20080091276 | Deusch et al. | Apr 2008 | A1 |
| 20080109017 | Herweck et al. | May 2008 | A1 |
| 20080113001 | Herweck et al. | May 2008 | A1 |
| 20080128932 | Hopman | Jun 2008 | A1 |
| 20080172071 | Barker | Jul 2008 | A1 |
| 20080242850 | Kim | Oct 2008 | A1 |
| 20080255593 | St-Germain | Oct 2008 | A1 |
| 20090018479 | McCarthy | Jan 2009 | A1 |
| 20090035341 | Wagener et al. | Feb 2009 | A1 |
| 20090036996 | Roeber | Feb 2009 | A1 |
| 20090068250 | Gravagna et al. | Mar 2009 | A1 |
| 20090105526 | Piroli Torelli et al. | Apr 2009 | A1 |
| 20090163936 | Yang et al. | Jun 2009 | A1 |
| 20090187197 | Roeber et al. | Jul 2009 | A1 |
| 20090192530 | Adzich et al. | Jul 2009 | A1 |
| 20090204129 | Fronio | Aug 2009 | A1 |
| 20090216338 | Gingras et al. | Aug 2009 | A1 |
| 20090270999 | Brown | Oct 2009 | A1 |
| 20090281558 | Li | Nov 2009 | A1 |
| 20090318752 | Evans et al. | Dec 2009 | A1 |
| 20100082102 | Govil | Apr 2010 | A1 |
| 20100104608 | Abuzaina et al. | Apr 2010 | A1 |
| 20100318108 | Datta et al. | Dec 2010 | A1 |
| 20110015760 | Kullas | Jan 2011 | A1 |
| 20110144667 | Horton et al. | Jun 2011 | A1 |
| 20110190795 | Hotter et al. | Aug 2011 | A1 |
| 20110238094 | Thomas et al. | Sep 2011 | A1 |
| 20110251699 | Ladet | Oct 2011 | A1 |
| 20110257666 | Ladet et al. | Oct 2011 | A1 |
| 20110311608 | Roorda | Dec 2011 | A1 |
| 20110320009 | Ladet | Dec 2011 | A1 |
| 20120016388 | Houard et al. | Jan 2012 | A1 |
| 20120022242 | Domard | Jan 2012 | A1 |
| 20120029537 | Mortarino | Feb 2012 | A1 |
| 20120065727 | Reneker et al. | Mar 2012 | A1 |
| 20120082712 | Stopek et al. | Apr 2012 | A1 |
| 20120116425 | Intoccia et al. | May 2012 | A1 |
| 20120150204 | Mortarino et al. | Jun 2012 | A1 |
| 20120165937 | Montanari et al. | Jun 2012 | A1 |
| 20120179175 | Hammell | Jul 2012 | A1 |
| 20120179176 | Wilson et al. | Jul 2012 | A1 |
| 20120197415 | Montanari et al. | Aug 2012 | A1 |
| 20130164311 | DeCarlo | Jun 2013 | A1 |
| 20140044861 | Boey et al. | Feb 2014 | A1 |
| 20140364684 | Lecuivre | Dec 2014 | A1 |
| Number | Date | Country |
|---|---|---|
| 759066 | Apr 2003 | AU |
| 1317836 | May 1993 | CA |
| 201879864 | Jun 2011 | CN |
| 19544162 | Apr 1997 | DE |
| 19718903 | Dec 1997 | DE |
| 19751733 | Dec 1998 | DE |
| 19832634 | Jan 2000 | DE |
| 10019604 | Oct 2001 | DE |
| 10120942 | Oct 2001 | DE |
| 10043396 | Jun 2002 | DE |
| 0194192 | Sep 1986 | EP |
| 0248544 | Dec 1987 | EP |
| 0263360 | Apr 1988 | EP |
| 0276890 | Aug 1988 | EP |
| 0372969 | Jun 1990 | EP |
| 0531742 | Mar 1993 | EP |
| 544485 | Jun 1993 | EP |
| 0552576 | Jul 1993 | EP |
| 0611561 | Aug 1994 | EP |
| 614650 | Sep 1994 | EP |
| 0621014 | Oct 1994 | EP |
| 0625891 | Nov 1994 | EP |
| 0637452 | Feb 1995 | EP |
| 0664132 | Jul 1995 | EP |
| 0705878 | Apr 1996 | EP |
| 0719527 | Jul 1996 | EP |
| 0774240 | May 1997 | EP |
| 0797962 | Oct 1997 | EP |
| 0800791 | Oct 1997 | EP |
| 827724 | Mar 1998 | EP |
| 0836838 | Apr 1998 | EP |
| 0847727 | Jun 1998 | EP |
| 0876808 | Nov 1998 | EP |
| 0895762 | Feb 1999 | EP |
| 898944 | Mar 1999 | EP |
| 1017415 | Jul 2000 | EP |
| 1036545 | Sep 2000 | EP |
| 1052319 | Nov 2000 | EP |
| 1055757 | Nov 2000 | EP |
| 1090590 | Apr 2001 | EP |
| 1 216 717 | Jun 2002 | EP |
| 1 216 718 | Jun 2002 | EP |
| 0693523 | Nov 2002 | EP |
| 1315468 | Jun 2003 | EP |
| 1382728 | Jan 2004 | EP |
| 1484070 | Dec 2004 | EP |
| 1561480 | Aug 2005 | EP |
| 1645232 | Apr 2006 | EP |
| 1674048 | Jun 2006 | EP |
| 1691606 | Aug 2006 | EP |
| 1782848 | May 2007 | EP |
| 2 005 894 | Dec 2008 | EP |
| 2 008 595 | Dec 2008 | EP |
| 2229918 | Sep 2010 | EP |
| 2244853 | Apr 1975 | FR |
| 2257262 | Aug 1975 | FR |
| 2 308 349 | Nov 1976 | FR |
| 2453231 | Oct 1980 | FR |
| 2612392 | Sep 1988 | FR |
| 2715309 | Jul 1995 | FR |
| 2715405 | Jul 1995 | FR |
| 2 724 563 | Mar 1996 | FR |
| 2730406 | Aug 1996 | FR |
| 2744906 | Aug 1997 | FR |
| 2766698 | Feb 1999 | FR |
| 2771622 | Jun 1999 | FR |
| 2773057 | Jul 1999 | FR |
| 2774277 | Aug 1999 | FR |
| 2779937 | Dec 1999 | FR |
| 2859624 | Mar 2005 | FR |
| 2863277 | Jun 2005 | FR |
| 2876020 | Apr 2006 | FR |
| 2884706 | Oct 2006 | FR |
| 2929834 | Oct 2009 | FR |
| 2953709 | Jun 2011 | FR |
| 1174814 | Dec 1969 | GB |
| 2 051 153 | Jan 1981 | GB |
| 2306110 | Apr 1997 | GB |
| H0332677 | Feb 1991 | JP |
| H05237128 | Sep 1993 | JP |
| H09137380 | May 1997 | JP |
| H11146888 | Jun 1999 | JP |
| 2008538300 | Oct 2008 | JP |
| 2011078767 | Apr 2011 | JP |
| 8902445 | Mar 1989 | WO |
| 8908467 | Sep 1989 | WO |
| 9009769 | Sep 1990 | WO |
| 9012551 | Nov 1990 | WO |
| 9206639 | Apr 1992 | WO |
| 9220349 | Nov 1992 | WO |
| 9311805 | Jun 1993 | WO |
| 9310731 | Jun 1993 | WO |
| 9318174 | Sep 1993 | WO |
| 9417747 | Aug 1994 | WO |
| 9507666 | Mar 1995 | WO |
| 9518638 | Jul 1995 | WO |
| 9532687 | Dec 1995 | WO |
| 9603091 | Feb 1996 | WO |
| 9608277 | Mar 1996 | WO |
| 9609795 | Apr 1996 | WO |
| 9614805 | May 1996 | WO |
| 9641588 | Dec 1996 | WO |
| 9735533 | Oct 1997 | WO |
| 9835632 | Aug 1998 | WO |
| 9849967 | Nov 1998 | WO |
| 9905990 | Feb 1999 | WO |
| 9906079 | Feb 1999 | WO |
| 9906080 | Feb 1999 | WO |
| 9951163 | Oct 1999 | WO |
| 0016821 | Mar 2000 | WO |
| 0067663 | Nov 2000 | WO |
| 0115625 | Mar 2001 | WO |
| 0180773 | Nov 2001 | WO |
| 0181667 | Nov 2001 | WO |
| WO 0192322 | Dec 2001 | WO |
| 02007648 | Jan 2002 | WO |
| 0217853 | Mar 2002 | WO |
| 02078568 | Oct 2002 | WO |
| WO 02102276 | Dec 2002 | WO |
| 03002168 | Jan 2003 | WO |
| 2004004600 | Jan 2004 | WO |
| 2004071349 | Aug 2004 | WO |
| 2004078120 | Sep 2004 | WO |
| 2004103212 | Dec 2004 | WO |
| 200511280 | Feb 2005 | WO |
| 2005013863 | Feb 2005 | WO |
| 2005018698 | Mar 2005 | WO |
| WO 2005044285 | May 2005 | WO |
| 2005048708 | Jun 2005 | WO |
| 2005105172 | Nov 2005 | WO |
| 2006018552 | Feb 2006 | WO |
| 2006023444 | Mar 2006 | WO |
| 2007042281 | Apr 2007 | WO |
| 2007048099 | Apr 2007 | WO |
| 2009031035 | Mar 2009 | WO |
| 2009031047 | Mar 2009 | WO |
| 2009071998 | Jun 2009 | WO |
| WO 2009111282 | Sep 2009 | WO |
| 2009156866 | Dec 2009 | WO |
| WO 2009156866 | Dec 2009 | WO |
| WO 2010042540 | Apr 2010 | WO |
| WO 2010043978 | Apr 2010 | WO |
| 2011007062 | Jan 2011 | WO |
| 2011026987 | Mar 2011 | WO |
| 2011038740 | Apr 2011 | WO |
| Entry |
|---|
| Wikipedia, Ammonium Hydroxide, 2012; https://en.wikipedia.org/wiki/Ammonia_solution. |
| Lu et al., Degradation of covalently cross-linked carboxymethyl chitosan and its potential application for peripheral nerve regeneration, 2007, European Polymer Journal, 43.9, pp. 3807-3818. |
| International Written Opinion for PCT-EP2013-066238 dated Feb. 3, 2015 (Year: 2015). |
| International Search Report for PCT/EP13/066238 date of completion is Oct. 24, 2013 (4 pages). |
| Doillon, C.J., et al., Collagen-based wound dressings: control of the pore structure and morphology, J. Biomed. Mater. Res., Oct. 1986, pp. 1219-1228, vol. 20(8). |
| Schoof, H. et al., Control of Pore Structure and Size in Freeze-Dried Collagen Sponges, Journal of Biomedical Materials Research, May 2001, pp. 352-357, vol. 58, No. 4. |
| European Office Action dated Mar. 31, 2017 in corresponding European Patent Application No. 13745399.9, 5 pages. |
| Ellouali, M. et al., “Antitumor Activity of Low Molecular Weight Fucans Extracted from Brown Seaweed Ascophyllum nodosum,” Anticancer Res., Nov.-Dec. 1993, pp. 2011-2020, 12 (6A). |
| Malette, W. G. et al., “Chitosan, A New Hemostatic,” Ann Th. Surg., Jul. 1983, pp. 55-58, 36. |
| Langenbech, M. R. et al., “Comparison of biomaterials in the early postoperative period,” Surg Endosc., May 2003, pp. 1105-1109, 17 (7). |
| Bracco, P. et al., “Comparison of polypropylene and polyethylene terephthalate (Dacron) meshes for abdominal wall hernia repair: A chemical and morphological study,” Hernia, 2005, pp. 51-55, 9 (1), published online Sep. 2004. |
| Klinge, U. et al., “Foreign Body Reaction to Meshes Used for the Repair of Abdominal Wall Hernias,” Eur J. Surg, Sep. 1999, pp. 665-673, 165. |
| Logeart, D. et al., “Fucans, sulfated polysaccharides extracted from brown seaweeds, inhibit vascular smooth muscle cell proliferation. II. Degradation and molecular weight effect,” Eur. J. Cell. Biol., Dec. 1997, pp. 385-390, 74(4). |
| Haneji, K. et al., “Fucoidan extracted from Cladosiphon Okamuranus Tokida Induces Apoptosis of Human T-cell Leukemia Virus Type 1-Infected T-Cell Lines and Primary Adult T-Cell Leukemia Cells,” Nutrition and Cancer, 2005, pp. 189-201, 52(2), published online Nov. 2009. |
| Junge, K. et al., “Functional and Morphologic Properties of a Modified Mesh for Inguinal Hernia Repair,” World J. Surg., Sep. 2002, pp. 1472-1480, 26. |
| Klinge, U. et al., “Functional and Morphological Evaluation of a Low-Weight, Monofilament Polypropylene Mesh for Hernia Repair,” J. Biomed. Mater. Res., Jan. 2002, pp. 129-136, 63. |
| Welty, G. et al., “Functional impairment and complaints following incisional hernia repair with different polypropylene meshes,” Hernia, Aug. 2001; pp. 142-147, 5. |
| Varum, K. et al., “In vitro degradation rates of partially N-acetylated chitosans in human serum,” Carbohydrate Research, Mar. 1997, pp. 99-101, 299. |
| Haroun-Bouhedja, F. et al., “In Vitro Effects of Fucans on MDA-MB231 Tumor Cell Adhesion and Invasion,” Anticancer Res., Jul.-Aug. 2002, pp. 2285-2292, 22(4). |
| Scheidbach, H. et al., “In vivo studies comparing the biocompatibility of various polypropylene meshes and their handling properties during endoscopic total extraperitoneal (TEP) patchplasty: An experimental study in pigs,” Surg. Endosc., Feb. 2004, pp. 211-220,18(2). |
| Blondin, C. et al., “Inhibition of Complement Activation by Natural Sulfated Polysaccharides (Fucans) from Brown Seaweed,” Molecular Immuol., Mar. 1994, pp. 247-253, 31(4). |
| Zvyagintseva, T. et al., “Inhibition of complement activation by water-soluble polysaccharides of some far-eastern brown seaweeds,” Comparative Biochem and Physiol, Jul. 2000, pp. 209-215,126(3). |
| Rosen, M. et al., “Laparoscopic component separation in the single-stage treatment of infected abdominal wall prosthetic removal,” Hernia, 2007, pp. 435-440, 11, published online Jul. 2007. |
| Amid, P., “Lichtenstein tension-free hernioplasty: Its inception, evolution, and principles,” Hernia, 2004; pp. 1-7, 8, published online Sep. 2003. |
| Boisson-Vidal, C. et al., “Neoangiogenesis Induced by Progenitor Endothelial Cells: Effect of Fucoidan From Marine Algae,” Cardiovascular & Hematological Agents in Medicinal Chem., Jan. 2007, pp. 67-77, 5(1). |
| O'Dwyer, P. et al., “Randomized clinical trial assessing impact of a lightweight or heavyweight mesh on chronic pain after inguinal hernia repair,” Br. J. Surg., Feb. 2005, pp. 166-170, 92(2). |
| Muzzarelli, R. et al., “Reconstruction of parodontal tissue with chitosan,” Biomaterials, Nov. 1989, pp. 598-604, 10. |
| Haroun-Bouhedja, F. et al., “Relationship between sulfate groups and biological activities of fucans,” Thrombosis Res., Dec. 2000, pp. 453-459, 100(5). |
| Blondin, C. et al., “Relationships between chemical characteristics and anticomplementary activity of fucans,” Biomaterials, Mar. 1996, pp. 597-603, 17(6). |
| Strand, S. et al., “Screening of Chitosans and Conditions for Bacterial Flocculation,” Biomacromolecules, Mar. 2001, 126-133, 2. |
| Kanabar, V. et al., “Some structural determinants of the antiproliferative effect of heparin-like molecules on human airway smooth muscle,” Br. J. Pharmacol., Oct. 2005, pp. 370-777, 146(3). |
| Hirano, S. et al., “The blood biocompatibility of chitosan and N-acylchitosans,” J. Biomed. Mater. Res., Apr. 1985, 413-417, 19. |
| Rao, B. et al., “Use of chitosan as a biomaterial: Studies on its safety and hemostatic potential,” J. Biomed. Mater. Res., Jan. 1997, pp. 21-28, 34. |
| Prokop, A. et al., “Water Soluble Polymers for Immunoisolation I: Complex Coacevation and Cytotoxicity,” Advances in Polymer Science, Jul. 1998, pp. 1-51, 136. |
| Collins, R. et al., “Use of collagen film as a dural substitute: Preliminary animal studies,” Journal of Biomedical Materials Research, Feb. 1991, pp. 267-276, vol. 25. |
| Preliminary Search Report from French Patent Office dated Dec. 20, 2006, 3 pages. |
| Tolaimate, A., et al. “Contribution to the preparation of chitins and chitosans with controlled physico-chemical properties.” Polymer, Dec. 2003, pp. 7939-7952, 44 (26). |
| O'Brien, F. J. et al., “Influence of freezing rate on pore structure in freeze-dried collagen-GAG scaffolds” Biomaterials, Mar. 2004, pp. 1077-1086, vol. 25, Issue 6. |
| Lamarque, G. et al., “Comparative Study of the Second and Third Heterogeneous Deacetylations of alpha- and beta-Chitins in a Multistep Process” Biomacromolecules, Sep.-Oct. 5, 2004, pp. 1899-1907, 5. |
| Lamarque, G. et al., Comparative Study of the First Heterogeneous Deacetylation of alpha- and beta-Chitins in a Multistep Process Biomacromolecules May-Jun. 2004, 992-1001, 5. |
| Lamarque, G. et al, “New Route of Deacetylation of alpha- and beta-Chitins by Means of Freeze-Pump Out-Thaw Cycles” Biomacromolecules, May-Jun. 2005, pp. 1380-1388, 6. |
| Number | Date | Country | |
|---|---|---|---|
| 20150158209 A1 | Jun 2015 | US |
