Patent Application
20180236133
The invention relates to production of matrix product, more particularly, to extracellular matrix (ECM) product useable in breast implant surgery.
In breast reconstruction surgery, silicone materials have been conventionally used but silicone has slippery characteristics, and slipperiness of materials being used in breast reconstruction surgery is a disadvantage. Some work has been done on silicone-based materials to try to reduce the slipperiness. Other work has been done in directions of exploring non-silicone materials to use in breast reconstruction surgery.
In the direction of textured exterior surfaces for breast implants, the patent literature includes the following:
U.S. Pat. No. 6,692,527 for “Non-rotating breast implant,” by Bellin, et al., issued Feb. 17, 2004.
U.S. Pat. No. 7,105,116 for “Non-rotating breast implant,” by Bellin, et al., issued Sep. 12, 2006.
U.S. Pat. No. 8,043,373 for “All-barrier elastomeric gel-filled breast prosthesis,” by Schuessler, et al., issued Oct. 25, 2011 to Allergan, Inc.
U.S. Pat. Pub. 20120101574 for “Implantable materials,” by Goraltchouk, et al. (Allergan), published Apr. 26, 2012.
U.S. Pat. No. 8,197,542 for “Self supporting implant in a human body and method for making the same without capsular contracture,” by Becker, issued Jun. 12, 2012.
U.S. Pat. No. 8,313,527 for “Soft prosthesis shell texturing method,” by Powell, et al., issued Nov. 20, 2012 to Allergan, Inc.
U.S. Pat. Pub. 20140180412 for “Device and method for making a variable surface breast implant,” by Nieto, et al. (Allergan), published Jun. 26, 2014.
U.S. Pat. Pub. 20140242258 for “Implantable materials,” by Goraltchouk, et al. (Allergan), published Aug. 28, 2014.
U.S. Pat. No. 9,138,310 for “Soft prosthesis shell texturing method,” by Powell, et al., issued Sep. 22, 2015, to Allergan, Inc.
U.S. Pat. Pub. 20140305854 for “Variable surface breast implant,” by Schuessler, et al. (Allergan), published Oct. 29, 2015.
U.S. Pat. Pub. 20150327986 for “Textured breast implant and methods of making same,” by Nieto, et al. (Allergan), published Nov. 19, 2015.
U.S. Pat. No. 9,688,006 for “Device and method for making a variable surface breast implant,” by Nieto, et al. (Allergan), issued Jun. 27, 2017 to Allergan, Inc.
U.S. Pat. Pub. 20170290652 for “Device and method for making a variable surface breast implant,” by Nieto, et al. (Allergan), published Oct. 12, 2017.
Some uses of certain ECM products have been described in the literature for breast reconstruction products. See. e.g., Matheny et al., “Breast implants and compositions of extracellular matrix,” US 2008/0281419, published Nov. 13, 2008; Matheny, “Breast implants and compositions of extracellular matrix,” US 2010/0010627, published Jan. 14, 2010; Ward, et al., “Tissue scaffolds derived from forestomach extracellular matrix,” US 20140335144, published Nov. 13, 2014; Codori-Hurff, et al., “Mastopexy and breast reconstruction prostheses and method,” US 20120158134, published Jun. 21, 2012; Badylak, et al., “Extracellular matrix mesh coating,” US 20150297798, published Oct. 22, 2015.
There remain unmet needs for non-slippery products suitable for use in breast reconstruction surgery.
The invention addresses the aspect of the prior art that thus far, conventional ECM has been relatively low in tackiness, and generally lacking in self-cohesiveness, and more along the lines of being characterized by slipperiness. An objective of the invention is to produce ECM useable in surgery (especially breast implant surgery) and having improved tackiness compared to conventional ECM product.
The invention in a preferred embodiment provides a method of producing tacky ECM product, comprising steps of: mixing glycosaminoglycans (GAGs) and collagen (such as, e.g., micronized collagen) to form a collagen mixture (such as, e.g., a mixing step that comprises adding GAGs into a container having collagen therein to form the collagen mixture); followed by homogenizing the collagen mixture to form a slurry; lyophilizing the slurry until the slurry is completely frozen; followed by after the slurry is completely frozen, drying the frozen slurry to form a matrix, such as, e.g., inventive methods further comprising, before the adding of GAGs into the container having collagen therein, performing a step of introducing a mass of collagen into the container (such as, e.g., a container of acetic acid (ethanoic acid); a container of hydrochloric acid (HCl; muriatic acid); a container of formic acid (methanoic acid); a container of propanoic acid (propionic acid); etc.); inventive methods wherein the step of adding GAGs comprises adding GAGs drop-wise; inventive methods further comprising, after homogenizing the collagen mixture to form the slurry, performing a step of degassing the slurry before lyophilizing the slurry; inventive methods wherein the GAGs comprise Hyaluronic acid (HA/HyA); inventive methods wherein the GAGs comprise Chondroitin-6-sulfate (C6S); inventive methods wherein the GAGs comprise Hyaluronic acid and C6S; inventive methods wherein the GAGs comprise one or more of selected from the group consisting of: Hyaluronic acid (HA): Chondroitin-6-sulfate (C6S); Keratin sulfate; Heparin; Heparin sulfate; and Fibronectin; inventive methods wherein the drying step comprises activating a vacuum, wherein the vacuum activation is performed only after the slurry is completely frozen; inventive methods wherein during the drying step, the slurry is disposed on a tray (such as, e.g., methods wherein during the drying step, the tray temperature is in a range of −45 to −3° C.; methods wherein during the drying step, no part of the slurry is permitted to reach or exceed 0° C.; etc.), and other inventive methods.
In another preferred embodiment, the invention provides a surgically-implantable product, comprising an ECM that has a tackiness that is self-cohesive, preferably an ECM that comprises collagen (such as, e.g., bovine collagen, etc.), an ECM that comprises an envelope shape, etc.
The invention provides surgically-useable, relatively-tacky ECM product (such as, e.g., ECM product produced from collagen (such as, e.g., bovine collagen)), and methods (such as the methodology of Inventive Examples 1-2M1 hereinbelow) for producing such relatively-tacky ECM product.
Preferably the ECM is sufficiently tacky to be self-cohesive.
Tacky ECM product (especially self-cohesive ECM) according to the invention is useable in certain surgeries, especially in breast reconstruction surgery, where less-slippery ECM product is advantageous.
As may be appreciated with reference to
The following examples are by way of illustration, and are not intended to be limiting.
DDW [H2O (aq.)]—(dry distilled water/deionized H2O)
Glacial acetic acid
Decellularized, lyophilized micronized bovine type I collagen
Glycosaminoglycans (GAGs)
Homogenizer with cooling apparatus
Cooling apparatus
Lyophilizer and vacuum pump
Beakers and flasks
Matrices should be cut to appropriate product sizes (if necessary) and packaged.
Beakers and flasks
DDW [H2O (aq.)]—(dry distilled water/deionized H2O)
Glacial acetic acid [C2H4O2 (aq.)]
Decellularized, lyophilized micronized bovine type I collagen (s.)
Glycosaminoglycans (GAGs)
Industrial mixer
Cooling apparatus
Vacuum pump
Lyophilizer
a. Preparation of the cooling system and homogenization unit.
b. Production of the slurry
c. Agitation of the mixture: The mixture is agitated at a minimum rate of 10,000 rpm (maximum 24,000 rpm) for up to 2 hours. The purpose of this agitation step is to achieve complete homogenization. Balancing is wanted in this step between temperature of the slurry, time spent homogenizing, and the rate of the homogenization unit. This step's objective is complete homogenization, such that the slurry appears completely uniform and without particulate matter.
d. Degassing of the slurry: Degassing is essential for optimal matrix formation and organization, and can be achieved by introducing the slurry to a vacuum. One hour of degassing is sufficient. The purpose of the vacuum is to remove all the trapped gas within the liquid matrix and to essentially purify the slurry by removing air.
3. Lyophilization of slurry
The preferred relationship between the desired volume of slurry in milliliters (mL) and mass of glacial acetic acid in milligrams (mg) is:
3*desired volume (mL)slurry=mass (mg)acetic acid
An example of dilution of acetic acid during slurry preparation in Example 2 is:
1. Introduce 2.250 mg (2.250 g; ˜2.154 mL) glacial acetic acid to a 1 L beaker.
2. Add 750 mL (750 g) DDW and stir.
3. Set aside for later use.
The preferred relationship between the desired volume of slurry in milliliters (mL) and mass of micronized collagen in grams (g) is:
In an example according to Ex. 2C, 3.75 g collagen is introduced to the container slurry preparation according to Ex. 2B.
The preferred relationship between the desired volume of slurry in milliliters (mL) and mass of chondroitin-6-sulfate (C6S) in milligrams (mg) is:
The preferred relationship between the desired volume of slurry in milliliters (mL) and mass of hyaluronic acid (HA) in milligrams (mg) is:
10*desired volume (mL)slurry=mass (mg)HA
An example of slurry-preparation according to Exs. 2, 2F and 2G is as follows:
In the slurry-homogenization step of Example 2, for preparation of the cooling system and homogenization, cold rooms are one of the best ways to keep the temperature of the slurry at an acceptable level (18° C. or lower).
In the slurry-homogenization step of Example 2, for preparation of the cooling system and homogenization, an option for a sterile endothermic system consists of the vessel being introduced to a liquid bath, or homogenized inside a refrigeration unit. The bath must be able to remain liquid at cold temperatures, so water or propylene glycol is recommended as the solvent. By adding to the bath a coolant, an example of which is CO, (s.) [carbon dioxide, solid (dry ice)], the temperature of the heat sink can be kept as close as possible to 0° C. (273K).
For the agitation step in Example 2, agitation that has been found to be efficient (for the purpose of carrying out complete homogenization, such that the slurry appears completely uniform and without particulate matter) is homogenization at 15,000 rpm (or the max rate without overheating the slurry) for 30 to 60 minutes, and including a few short bursts of higher rates either throughout or at the end.
One method of achieving a vacuum in a step of introducing a slurry to a vacuum is to fill a vacuum-enabled Erlenmeyer flask with slurry, stopper the top, and pull vacuum on the contents of the flask.
Bubbles only appear in a slurry if gas is still trapped within the mix; this is a key indicator that the slurry contains gas, and that more degassing is needed. The longer the slurry is exposed to negative pressure, the less gas volume will exist within the slurry; therefore, as the degassing process approaches completion, the bubbles will become smaller and less numerous.
An indication of a fully purged slurry is lack of bubbles when exposed to the vacuum. Lack of bubbles in the slurry is used as an endpoint for the degassing step.
During the degassing process, preferably the lyophilizer is activated, and the tray temperature is set to −25° C. (228K), and the system is allowed to reach equilibrium.
Because the degassing step takes approximately 1 hour, it is optimal, during the degassing of the slurry, to begin a lyophilization acclimation process.
In the drying step, after the vacuum is activated, atmospheric pressure in the lyophilization chamber will decrease until the pressure in the system reaches maximum vacuum.
An atmospheric pressure value of 200 mtorr (0.00026 atm=0.00026 barr=26.67 Pa=0.00387 PSI) is sufficient. A stronger vacuum (less pressure) will increase efficiency.
In the drying step, at a point where the pressure in the system reaches maximum vacuum, set the tray temperature to −3° C. (270K) to encourage the sublimation of H2O.
NOTE: While the tray temperature can thusly be increased from −25° C. to −3° C., it is important not to let any volume of the slurry reach 0° C. or above. If any H2O is allowed to convert to liquid phase, the entire matrix will have to be refrozen and dried again before sterilization.
An example of removal of lyophilized slurry from a tray is as follows:
After removal of the lyophilized slurry, the solid is cut to appropriate product sizes (if necessary) and packaged.
A degassed slurry was produced according to Example 2. The degassed slurry was pipetted into a petri dish, and took the form of its container. A uniform consistency and lack of gas bubbles within the matrix were observed, which suggested that a high quality matrix would form during lyophilization.
Example 2N's degassed slurry in petri dish was subjected to lyophilization, and a dry matrix was produced. The dry matrix kept its shape and was easily removed from the petri dish using tweezers.
While the matrix keeps its shape, meanwhile it is also extremely porous and flexible, like a sponge.
A degassed slurry is produced according to Example 2. The degassed slurry is dispensed (such as, e.g., by pipetting; by pouring; by dispensing; etc.) into or onto a container (such as, e.g., a petri dish; a tray (preferably a metal tray); a mold; etc.).
In this example, a collagen-containing matrix useable as a breast implant has lower slipperiness (i.e., higher tackiness) than silicone implants sold by Allergan (Natrelle), Mentor, and Sientra.
A matrix is constructed according to an Example above (or a scaled-up variation thereof), in an envelope shape comprising a first open edge and a second open edge.
In this example, the matrix of Example 4 has a thickness of about 1 mm to 20 mm.
Into the envelope of Example 4 is placed a breast implant product (such as, e.g., a slippery implant, a textured implant, etc.) after which placement the first open edge is brought into contact with the second open edge, and sealing closure is manually accomplished by pressing two fingertips against each other with the envelope edges between the two pressed-together fingertips.
In this example according to Example 5, the volume of the implant product inside the envelope is in a range of about 1 mL to 500 mL, and the surface area defined by pressed-together edges is in a range of about 10 cm2 to 150 cm2.
In this example according to Example 5, a 300 cc breast implant is placed inside the matrix envelope, and the surface area defined by pressed-together edges is in a range of about 10 cm2 to 150 cm2.
A matrix sample that had been made by the inventors was subjected to “closure” experimentation. Pressures in a range of 18-998 grams applied for under 2 seconds were found to bring about closure. That a pressure as low as 100 grams was sufficient to accomplish closure is considered a unique and important characteristic of the inventive matrix; that closure was accomplished with even lower pressures, and as low as 18 grams of pressure, is considered to be a highly advantageous characteristic of the material.
The above described embodiments are set forth by way of example and are not limiting. It will be readily apparent that obvious modifications, derivations and variations can be made to the embodiments. Accordingly, the claims appended hereto should be read in their full scope including any such modifications, derivations and variations.
| Number | Date | Country | |
|---|---|---|---|
| 62462067 | Feb 2017 | US |
