CN116457035A - Tissue repair device and molding method - Google Patents

Abstract

Medical articles and methods for forming the same are disclosed. The medical article may take the form of a sponge having a three-dimensional shape including a reservoir. In one embodiment, the sponge is formed by placing a collagen slurry (optionally further comprising minerals) in a mold and lyophilizing the slurry. In one embodiment, an improved molding method for such medical articles includes forcing a slurry through a mold comprising a shape of a tube having a blockage connected to a sidewall of the tube via an arm extending from the sidewall to the blockage.

Description

Tissue repair device and molding method

Cross Reference to Related Applications

This application is an international application claiming the priority of U.S. provisional patent application No. 63/107618, filed 10/30 in 2020, U.S. design application serial No. 29/756,896, filed 11/24 in 2020, each of which is expressly incorporated herein by reference in its entirety.

Technical Field

The disclosed invention relates to medical articles and methods of molding the same. The medical article may be used as a device for repairing tissue defects.

Background

Medical articles for repairing tissue defects come in a variety of forms and have various uses. One such medical article is a bone void filler in the form of a three-dimensional sponge. The sponge (sponge) is typically in the form of a lyophilized composition of natural polymer. The sponge can be rehydrated, which renders the sponge pliable. The rehydration fluid may take various forms. Examples of rehydrating fluids are sterile water, whole blood, platelet rich plasma (platelet rich plasma, PRP) and bone marrow aspirate. Once the material has become pliable, the material may be manually placed directly into the bone defect, or placed into a syringe and dispensed into the bone defect.

Such sponges are typically formed by first forming a slurry of particles or fibers comprising water and a biocompatible polymer. The slurry may further comprise minerals, such as minerals known to promote bone growth. Examples of such minerals are hydroxyapatite, calcium phosphate, bioactive glass, bone granules, and mixtures thereof. The slurry is dispensed into a mold. The mold and slurry were then placed together in a freeze dryer and the slurry was lyophilized to produce a sponge. The sponge is then separated from the mold. Post-treatments, such as machining, may be performed prior to packaging and sterilization to ensure proper surface smoothness.

For many years, advances in medical articles for treating tissue defects have been increasing in ease of use. One such advancement is to provide the medical article in a form that allows the attending physician to easily rehydrate the medical article. One such commercially available product isOffered->Putty. The product is a dished sponge made from a lyophilized composition of about 80% by weight minerals and 20% by weight bovine collagen type I. The minerals are present in particulate form throughout the sponge. The mineral particles comprise about 15 wt% hydroxyapatite and 85 wt% beta-tricalcium phosphate, based on the total weight of the particles.

The Putty sponge is in the form of a disk with a reservoir that holds a rehydrating fluid. The reservoir is formed by a peripheral sidewall and a recessed surface (recessed surface). The article has a rectangular cross-section. To use this material, the physician dispenses a specified amount of rehydrated fluid directly into the dish. This has the advantage that the correct amount of rehydration fluid is used and that the rehydration fluid does not flow from the sponge to other surfaces. The physician then manipulates the material, either manually or by means of a tool, to uniformly rehydrate the sponge with a rehydrating fluid. The rehydrated material is then placed into the tissue defect manually or by means of a syringe.

Additional such medical articles are disclosed in US 7824703. This publication describes a medically useful article comprising a three-dimensional body comprising one or more implantable substances, wherein the body defines one or more reservoirs for receiving a quantity of biocompatible wetting liquid. In certain embodiments, the body is rupturable when wetted with a biocompatible liquid to form a conformable implantable material, such as a putty (putty), paste, or more flowable wetted implant material.

Although sponges including reservoirs or similar geometries may be desirable, they are not easily manufactured on a large scale.

Disclosure of Invention

When such slurries are lyophilized in a mold, bubbles, cracks and other defects tend to occur. Bubbles and defects typically occur at the mold/slurry interface because bubbles formed at the interface cannot be easily removed. This is most common at the bottom of the mould. These defects can lead to part scrap or additional time spent on post-processing. These drawbacks are exacerbated when forming sponges having a shape that includes a reservoir, as such shapes require additional mold surfaces to form the side walls and recessed surfaces that define the reservoir.

The molded slurry may be degassed by vacuum, but this may distort the molded part because air bubbles may be pulled from the molding slurry. Unexpected voids may also be created via vacuum degassing because the gas expands within the slurry due to the pressure drop. This is particularly problematic because the lyophilized sponge relies on a liquid (typically water) to act as a porogen. The bubble porogen distorts the pores created by the liquid. Degassing is also inefficient because it adds additional process steps to the manufacturing process.

These difficulties can be overcome by applying the methods of the present invention and forming the medical articles of the present invention described herein.

In one embodiment, the medical article comprises a sponge in the form of a three-dimensional shape. The three-dimensional shape includes a reservoir capable of holding a liquid, the reservoir being defined by a sidewall and a recessed surface, wherein the sidewall includes a plurality of cuts extending from a top surface thereof toward the recessed surface, wherein the plurality of cuts extend across a width of the sidewall.

The cut-out may be formed as a result of the molding process described herein. In one embodiment, a method of forming a medical article comprising a sponge comprises the steps of:

a. Providing a mold comprising

i. A tube comprising a first open end, a second open end, and a wall extending therebetween, an

A stopper present in the tube, wherein the stopper is connected to the wall via an arm extending from the wall to the stopper,

b. providing a slurry of the material to be treated,

c. forcing the slurry from the first open end through the tube to the second open end and past the obstruction to substantially fill the mold with slurry, an

d. Lyophilizing the slurry present in the mold, thereby forming a sponge.

By applying the method of the present invention and forming the medical article of the present invention described herein, various benefits may be obtained, including fewer part defects, lower scrap rates, increased manufacturing throughput, lower manufacturing costs, reduced post-processing time, greater flexibility in material composition and mineral loading in the slurry, improved mechanical properties of the medical article, more consistency in final handling properties after rehydration, lower likelihood of fluid leakage, and the ability to mold new geometries.

Drawings

Fig. 1 depicts a top perspective view of a medical article according to one embodiment of the invention.

Fig. 2 depicts a bottom perspective view of the medical article depicted in fig. 1.

Fig. 3 depicts a top view of a mold that may be used with methods according to embodiments of the present invention.

Fig. 4 depicts a cross-section of the mold depicted in fig. 3.

Fig. 5 depicts a top view of a mold that may be used with methods according to embodiments of the present invention.

Detailed Description

The medical articles described herein include sponges in the form of three-dimensional shapes. The three-dimensional shape includes a reservoir for holding a liquid. The liquid is typically a rehydration fluid for a sponge. For example, the rehydration fluid may be a sterile fluid, whole blood, a blood component (e.g., platelet rich plasma), or bone marrow aspirate.

As described herein, the sponge can be formed by filling a mold with a slurry and lyophilizing the slurry in the mold. In one embodiment, the slurry comprises water and fibers. In one embodiment, the fibers are polymeric fibers. In one embodiment, the polymeric fibers are fibers of natural polymers. In one embodiment, the polymeric fibers are fibers of natural or synthetic biopolymers. In one embodiment, the slurry comprises a soluble biopolymer of natural or synthetic origin. Examples of polymer fibers are fibers of collagen, chitosan, alginate or hyaluronic acid. The fibers are preferably hydrophilic.

In one embodiment, the slurry or medical article comprises polymeric fibers. In one embodiment, the medical article or slurry comprises collagen fibers. Collagen fibers are fibers of collagen and are insoluble in aqueous liquids at pH 3.5. In one embodiment, the collagen fibers are natural collagen fibers, not reconstituted collagen fibers. In one embodiment, the average length of the polymer fibers is from 1mm to 15mm. In one embodiment, the average length of the polymer fibers is from 0.5mm to 10mm. In one embodiment, the average length of the polymer fibers is at least 0.5mm, at least 1mm, at least 2mm, at least 3mm, or at least 4mm. In one embodiment, the average length of the polymer fibers is at most 15mm, at most 12mm, at most 10mm, at most 9mm, at most 8mm, at most 7mm, at most 6mm, at most 5mm, or at most 4mm.

The natural collagen fibers may have a fiber length of 50mm or more. The length of the collagen fibers can be controlled by known processing methods. For example, the average fiber length can be controlled by centrifugally grinding the collagen fibers using a cutting head of suitable gap size. A cutter head gap size of 5mm produces an average fiber length of 5mm. If the centrifugal grinding cutter head gap size is unknown or substantially non-uniform, an optical comparator or optical microscope may be used to measure the average fiber length.

In one embodiment, the sponge or medical article further comprises acid-soluble collagen. Acid-soluble collagen is collagen in a form that is insoluble in an aqueous liquid at a pH of 6.5 and soluble in an aqueous liquid at a pH of 4. To dissolve collagen in the solution, the pH was lowered to 2 to 4. However, once in solution, the pH can be raised to 6.5 without allowing collagen to precipitate out of solution. The acid-soluble collagen is introduced into the liquid as particles or powder to form a slurry.

In one embodiment, the acid-soluble collagen is processed without the aid of an enzyme, and is thus non-enzymatically processed acid-soluble collagen. Non-enzymatically processed acid-soluble collagen can be produced by grinding a cleaned collagen source material, such as hide (hide) or skin (skin). In general, collagen for use in the present invention may be obtained from any suitable animal source, such as bovine, porcine, fish, ovine, caprine or other sources. Procollagen proteins resulting from non-enzymatic processing cannot undergo spontaneous fibrosis under physiological conditions.

In one embodiment, the weight ratio of collagen fibers to acid soluble collagen in the sponge or slurry is from 25:75 to 75:25. In one embodiment, the dry sponge or slurry comprises 10 to 75 wt% acid soluble collagen and 25 to 90 wt% collagen fibers, respectively, based on the total amount of collagen in the dry sponge or slurry.

In one embodiment, the slurry or medical article further comprises minerals. Minerals may be present as particles or fibers. After lyophilization of the slurry, the minerals are supported by and retained in the polymer fiber network. In one embodiment, the mineral is present as particles having an average particle size of 0.05mm to 5 mm. In one embodiment, the mineral is present as particles having an average particle size of at least 0.05mm, at least 0.1mm, at least 0.2mm, at least 0.3mm, at least 0.4mm, or at least 0.5 mm. In one embodiment, the mineral is present as particles having an average particle size of at most 5mm, at most 4mm, at most 3mm, at most 2mm, at least 1mm, or at least 0.5 mm.

In one embodiment, the slurry is highly resistant to flow. In one embodiment, the slurry may be placed into a cylinder having two open ends at room temperature and the filled cylinder rotated on its wall such that the longitudinal axis of the cylinder faces horizontally and will be substantially free of slurry leakage for at least 30 seconds. In one embodiment, the slurry may be placed into a cylinder having two open ends at room temperature and the filled cylinder rotated on its wall such that the longitudinal axis of the cylinder faces horizontally and will be substantially free of slurry leakage for at least 30 seconds, at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, or at least 1 hour. In one embodiment, the mineral comprises hydroxyapatite, bioactive glass, tricalcium phosphate (e.g., alpha-tricalcium phosphate or beta-tricalcium phosphate), or bone particles. The bone particles may be inorganic bone particles, autologous bone particles, allogeneic bone particles, or xenogeneic bone particles, or a combination thereof. Minerals may be monophasic or biphasic. In one embodiment, the dry sponge or slurry comprises from 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% to 95 wt%, 94 wt%, 93 wt%, 92 wt%, 91 wt%, 90 wt%, 89 wt%, 88 wt%, 87 wt%, 86 wt% or 85 wt% of minerals, respectively, based on the total weight of the dry sponge or slurry solids. In one embodiment, the dry sponge or slurry comprises collagen and a mineral, wherein the collagen is present at from 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, or 15 wt% to 30 wt%, 29 wt%, 28 wt%, 27 wt%, 26 wt%, 25 wt%, 24 wt%, 23 wt%, 22 wt%, 21 wt%, 20 wt%, 19 wt%, 18 wt%, 17 wt%, or 16 wt%, based on the total weight of the dry sponge or slurry solids, respectively.

The medical article may be formed by first forming a slurry. In one embodiment, the slurry comprises water and polymer fibers. In one embodiment, the slurry further comprises other ingredients, such as acid-soluble collagen or minerals. The working pH range of a slurry containing collagen fibers and/or acid soluble collagen is typically 2 to 8. In one embodiment, the slurry has a pH of 4.5 to 8. In one embodiment, the slurry further comprises an acid, base, or buffer. Typically, an acid or base is added to the slurry to bring the slurry to the desired pH. In the case of collagen-containing slurries, the viscosity of the slurry depends on factors such as the pH of the slurry, the fiber length of the collagen fibers, the ratio of fibrous collagen to soluble collagen, and the solids content of the slurry.

In one embodiment, the slurry has a solids content of 2 to 30 wt%, based on the total weight of the slurry. The solids content is left after removal of the liquid component of the slurry, e.g. after freeze-drying the slurry. In one embodiment, the slurry has a solids content of at least 2 wt%, 5 wt%, or 10 wt%, based on the total weight of the slurry. In one embodiment, the slurry has a solids content of up to 40 wt%, 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, or 10 wt%, based on the total weight of the slurry. The solids content by weight of the slurry when minerals are present in the slurry is generally higher than the solids content by weight of the slurry when minerals are not present in the slurry. In one embodiment, the slurry does not contain minerals and the solids content of the slurry is from 2 wt% to 10 wt%. In one embodiment, the slurry comprises minerals and the solids content of the slurry is from 10 wt% to 40 wt%.

In one embodiment, the slurry is introduced into a mold and lyophilized to form a sponge. This method of forming a sponge generally results in a sponge having randomly arranged fibers. After lyophilization, the sponge may be crosslinked. In one embodiment, crosslinking is performed without the use of chemicals, such as by dehydration thermal crosslinking of a collagen sponge. In one embodiment, crosslinking is performed using a chemical (e.g., glutaraldehyde). The final device may be obtained by cutting the material after crosslinking, for example by cutting the material with a laser or a mill.

In one embodiment, the medical article has a circular, oval, or polygonal footprint. In one embodiment, the general shape of the medical article is a cylinder, an elliptical cylinder, or a polyhedron.

In one embodiment, the medical article comprises at least one reservoir. In one embodiment, the reservoir is defined by a recessed surface and a sidewall. The concave surface may be flat or curved. The recessed surface is generally positioned opposite the substrate surface. In one embodiment, the sidewall is a peripheral sidewall extending along a periphery of the medical article. In one embodiment, the sidewall is formed from a top surface, an inner sidewall surface, and an outer sidewall surface.

In one embodiment, the medical article comprises a sidewall comprising a cutout. In one embodiment, the at least one incision is created by a molding process used to form the medical article. Other cuts may also be made by the molding process or may be added during post-processing. The cut-out may have various shapes, such as square, rectangular, trapezoidal, partially circular or partially elliptical cross-sections. The cut typically starts at the top surface of the sidewall, extends through the entire sidewall, but does not reach the recessed surface. This allows the rehydration fluid to remain in the recessed surface defined by the sidewalls without escaping through the cut-outs. The incision can be used as an indicator of the proper amount of rehydration fluid that should be deposited in the reservoir to properly rehydrate the medical article.

A medical article according to an embodiment of the present invention is shown in fig. 1 and 2. The medical article comprises a sponge comprising a reservoir. The reservoir is formed by a concave surface 1 and side walls. The side wall is constituted by a plurality of surfaces 2a, 2b, 2c, 2d, the portion of surface 2e extending above the recessed surface 1 and the surfaces forming the cutouts 3, 4 and 5. The outer side wall is divided into two sections, a surface 2d, and a portion of the surface 2e extending above the recessed surface 1.

The concave surface 1 is substantially flat. In one embodiment, the concave surface 1 is concave (concave). The bottom surface 6 is substantially flat. The inner side wall is formed by a plurality of surfaces 2a and 2 b. The lower inner side wall surface 2a meets the concave surface 1 at an angle of about 93 degrees. The upper inner side wall surface 2b meets the lower inner side wall surface 2a at an angle of about 177 degrees such that the upper inner side wall surface 2b and the recess surface 1 are substantially perpendicular. The upper inner side wall surface 2b is divided into three sections by the cutouts 3, 4 and 5. The lower inner side wall surface 2a and the upper inner side wall surface 2b together form an inner side wall surface.

The concave surface 1 is present opposite the bottom surface 6. The bottom surface 6 forms the base of the medical article. The lower outer surface 2e meets the bottom surface 6 at an angle of about 87 degrees. The upper outer surface 2d extends from the lower outer surface 2e at an angle of 177 degrees such that the upper outer surface 2d and the bottom surface 6 are substantially perpendicular. The upper outer surface 2d is substantially perpendicular to the top surface 2c. The lower outer surface 2e and the upper outer surface 2d together form an outer surface. The portions of the upper outer surface 2d and the lower outer surface 2e extending above the recessed surface 1 together form an outer sidewall surface.

In one embodiment, the outer surface comprises a first surface and a second surface, wherein the surfaces meet at an angle of less than 180 degrees. In one embodiment, the outer surface comprises a first surface and a second surface, wherein the surfaces meet at an angle of 160 degrees to 179 degrees.

In one embodiment, the inner sidewall surface includes a first surface and a second surface, wherein the surfaces meet at an angle of less than 180 degrees. In one embodiment, the inner sidewall surface includes a first surface and a second surface, wherein the surfaces meet at an angle of 160 degrees to 179 degrees.

In one embodiment, the sidewall includes a surface that meets the recessed surface at an angle greater than 90 degrees. In one embodiment, the sidewall includes a surface that meets the recessed surface at an angle of 91 degrees to 110 degrees. In one embodiment, the outer surface comprises a surface that meets the bottom surface at an angle of 70 degrees to 89 degrees.

The top surface 2c, the upper inner side wall surface 2b and the upper outer surface 2d are divided into a plurality of sections by the cutouts 3, 4 and 5. The cut is formed as a result of the molding process described herein. As depicted, the edges of the cutout are rounded at the intersection of the cutout with the upper outer surface 2d and the upper inner sidewall surface 2 b. Otherwise, the angle formed is about 90 degrees to facilitate post-processing machining.

As depicted in fig. 1 and 2, the portion of the sidewall between the bottom and the cutout may be angled differently than the rest of the medical article in order to facilitate post-processing. For example, this portion of the device may include surfaces that intersect at about 90 degrees.

Fig. 3 and 4 depict top and cross-sections, respectively, of a mold suitable for forming a medical article shaped similar to the medical article depicted in fig. 1 and 2. The main difference between the medical article depicted in fig. 1 and 2 and the mold depicted in fig. 3 and 4 is that the depicted mold is unable to form a surface that meets at an angle less than or greater than 90 degrees. In contrast, the dies in fig. 3 and 4 are depicted such that all surfaces meet at a 90 degree angle and the corners are not rounded for simplicity. Although the corners are shown as non-rounded, the resulting medical article may still have a small radius resulting from the mold machining process.

As depicted in fig. 3, the mold 30 includes a circular wall 31 within which a circular obstruction 32 is present, less than the entire height of the mold. The blocking object 32 is supported in the mould by arms 33, 34, 35 connecting the blocking object 32 with the wall 31. The obstruction and arms thus together define open spaces 36, 37 and 38, which allow slurry to pass on the sides of the obstruction 31 and arms 33, 34, 35. The molds are typically present in a block pallet comprising a number of molds, as depicted in fig. 3 and 4.

Fig. 4 depicts a cross section A-A of the mold shown in fig. 3. The obstruction 32 and arms (not shown) are present at less than the full height of the mold. The mould comprises a tube with a circular inner surface 31. Thus, the interior of the tube generally comprises a cylindrical shape having a fully open end 39 and a partially occluded end 40. A slurry may be deposited in the end 39 to fill the mold. The concave surface of the medical article is formed against the top surface of the obstruction 32. Cutouts are formed around arms 33, 34, 35. The top surface of the sidewall is formed at the partially blocked end 40.

Typically, the mold is overfilled with slurry such that excess slurry is present on either end 39, 40 of the mold. The excess slurry was scraped off. Thereafter, the mold is placed on the tray, with the generally partially blocked end 40 facing the tray, and the mold and tray are placed together in a freeze dryer.

Fig. 5 depicts another embodiment of a mold. The mold depicted in fig. 5 may be suitable for forming a medical article comprising a substantially rectangular footprint having four cutouts in its sidewalls.

In one embodiment, the medical article further comprises a bioactive agent. The bioactive agent may be, for example, a steroid, an anti-inflammatory agent, an antibiotic, or another bioactive agent that may be used to treat a wound or inflammation. The bioactive agent may be present inside the sponge, for example, by soaking the sponge in the bioactive agent or by incorporating microparticles containing the bioactive agent upon formation of the sponge. The bioactive agent may also be present on the outer surface by forming a coating on the exterior of the sponge. The coating may be formed, for example, by dissolving the bioactive agent in a degradable synthetic polymer and coating the solution on the outer surface of the sponge. Suitable degradable synthetic polymers may include polylactic acid (PLA), polyglycolic acid (PGA), poly (lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyesteramide (PEA), or combinations or copolymers thereof.

In one embodiment, the medical article is a tissue repair device. In one embodiment, the tissue repair device is a bone void filler or is adapted to fill a defect in bone.

Examples

An aqueous slurry comprising natural insoluble collagen fibers (Semed F, DSM Biomedical) and acid soluble collagen (Semed S, DSM Biomedical) was prepared, the solids content of the aqueous slurry being 4.2 wt%. The aqueous slurry is then combined with minerals having a particle size of about 90-600 μm to produce a combined mixture of 83 wt% minerals and 17 wt% collagen, based on the total weight of minerals and collagen in the mixture. The mixture was then lyophilized in one of two different types of molds.

The first mold (hereinafter "open mold") has a circular cross-section and includes two open ends and a blockage, similar to the mold depicted in fig. 3. The obstruction is connected to the vessel wall via six arms. The geometry of the part produced by such a mold is similar to that depicted in fig. 1, but has six rather than three cutouts. The overall die dimensions were a diameter of 60mm and a height of 11 mm.

The second mold (hereinafter referred to as the "closed mold") has a rectangular cross section with rounded edges. The die is similar to the die depicted in fig. 5, but is closed at the end that includes the obstruction such that there are no arms and slurry cannot flow through the die. The resulting shape has no cut-outs in the side walls. The die dimensions were a length of about 67mm, a width of 47mm and a height of 8.3 mm.

Three samples of each of the open mold and the closed mold were formed as follows. The mold cavity is filled with the mixture and excess mixture is removed. The mold was then placed on a tray and lyophilized. After lyophilization, the samples were separated from the mold and visually analyzed by comparing the number of bubbles found in the surface of each sample. The results are shown in table 1.

Table 1: number of bubbles

The air bubbles detected when molding with an open mold are significantly less than those detected when molding with a closed mold. In addition, samples molded using open molds had smoother bottom surfaces, while closed mold samples had uneven bottom surfaces.

Additional description of exemplary embodiments

1. A medical article comprising a sponge in the form of a three-dimensional shape comprising a reservoir capable of holding a liquid, the reservoir being defined by a sidewall and a recessed surface, wherein the sidewall comprises a plurality of cuts extending from a top surface thereof toward the recessed surface, wherein the plurality of cuts extend across a width of the sidewall.

2. A medical article comprising a sponge in the form of a three-dimensional shape, the sponge comprising: the apparatus includes a base surface, a top surface, a recessed surface opposite the base surface, an outer surface extending between the base surface and the top surface, and an inner sidewall surface extending between the recessed surface and the top surface, wherein the three-dimensional shape includes a plurality of cuts extending from the top surface and through the inner sidewall surface and the outer surface.

3. A method of forming a medical article, the method comprising the steps of:

a. providing a mold, the mold comprising:

i. a tube comprising a first open end, a second open end and a wall extending therebetween, an

A blockage present in the tube,

b. a slurry is provided comprising water and fibers,

c. forcing the slurry from the first open end through the tube to the second open end and past the obstruction to substantially fill the mold with slurry, an

d. Lyophilizing the slurry present in the mold, thereby forming a medical article comprising a reservoir.

4. A method of forming a medical article comprising a sponge, the method comprising the steps of:

a. Providing a mold comprising

i. A tube comprising a first open end, a second open end and a wall extending therebetween, an

A stopper present in the tube, wherein the stopper is connected to the wall via an arm extending from the wall to the stopper,

b. a slurry is provided that includes water and,

c. forcing the slurry from the first open end through the tube to the second open end and past the obstruction to substantially fill the mold with slurry, an

d. Lyophilizing the slurry present in the mold, thereby forming a sponge.

5. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge or slurry comprises polymeric fibers.

6. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge or slurry comprises a biopolymer.

7. The medical article or method of any of the preceding exemplary embodiments, wherein the sponge or slurry comprises a soluble biopolymer of natural or synthetic origin.

8. The method of any of the preceding exemplary embodiments, further comprising the step of separating the sponge from the mold.

9. The method according to any of the preceding exemplary embodiments, further comprising the step of separating slurry that has not advanced through the first open end via a mold prior to lyophilization.

10. The method according to any of the preceding exemplary embodiments, further comprising the step of separating the slurry that has advanced through the second open end via a mold prior to lyophilization.

11. The method of any of the preceding exemplary embodiments, wherein the sponge comprises a reservoir and a sidewall comprising a cutout.

12. The method of any of the preceding exemplary embodiments, wherein the sponge comprises a reservoir formed by a sidewall and a recessed surface, and wherein the sidewall comprises a cutout.

13. The method according to any of the preceding exemplary embodiments, further comprising the step of crosslinking the sponge.

14. The method of any of the preceding exemplary embodiments, wherein the slurry comprises water and polymer fibers.

15. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge is based on a natural polymer.

16. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge is a collagen-based sponge.

17. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry or sponge comprises fibers of a natural polymer.

18. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry or sponge comprises fibers of a natural or synthetic biopolymer.

19. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry or sponge further comprises acid-soluble collagen.

20. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry or sponge comprises acid-soluble collagen and collagen fibers.

21. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry or sponge further comprises a mineral.

22. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge further comprises a mineral, and the mineral is present as particles having an average particle size of 0.05mm to 5mm, or 0.05mm to 2 mm.

23. The medical article or method of any one of the preceding exemplary embodiments, wherein the mineral is present as particles having an average particle size of at least 0.05mm, at least 0.1mm, at least 0.2mm, at least 0.3mm, at least 0.4mm, or at least 0.5 mm.

24. The medical article or method of any one of the preceding exemplary embodiments, wherein the mineral is present as particles having an average particle size of at most 5mm, at most 4mm, at most 3mm, at most 2mm, at least 1mm, or at most 0.5 mm.

25. The medical article or method of any of the preceding exemplary embodiments, wherein the dry sponge or slurry comprises 50 to 95 wt% minerals and 5 to 50 wt% collagen, respectively, based on the total weight of the dry sponge or slurry solids.

26. The medical article or method of any of the preceding exemplary embodiments, wherein the dry sponge or slurry comprises from 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, or 15 wt%, to 30 wt%, 29 wt%, 28 wt%, 27 wt%, 26 wt%, 25 wt%, 24 wt%, 23 wt%, 22 wt%, 21 wt%, 20 wt%, 19 wt%, 18 wt%, 17 wt%, or 16 wt% of collagen, respectively, based on the total weight of the dry sponge or slurry solids.

27. The medical article or method of any of the preceding exemplary embodiments, wherein the dry sponge or slurry comprises from 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% to 95 wt%, 94 wt%, 93 wt%, 92 wt%, 91 wt%, 90 wt%, 89 wt%, 88 wt%, 87 wt%, 86 wt%, or 85 wt% of minerals, respectively, based on the total weight of the dry sponge or slurry solids.

28. The medical article or method according to any one of the preceding exemplary embodiments, wherein the dry sponge or slurry comprises 10 to 75 wt.% acid soluble collagen and 25 to 90 wt.% collagen fibers, respectively, based on the total amount of collagen in the dry sponge or slurry.

29. The medical article or method of any one of the preceding exemplary embodiments, wherein the weight ratio of collagen fibers to acid soluble collagen in the sponge or slurry is from 25:75 to 75:25.

30. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge is crosslinked.

31. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge is formed by lyophilizing a slurry comprising collagen and water.

32. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge is formed by lyophilizing a slurry comprising acid-soluble collagen, collagen fibers, and water.

33. The medical article or method of any one of the preceding exemplary embodiments, wherein the sponge is formed by lyophilizing a slurry comprising acid-soluble collagen, collagen fibers, mineral particles, and water.

34. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry has a pH of 4.5 to 8.

35. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry further comprises an acid, a base, or a buffer.

36. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry has a solids content of 2 wt% to 30 wt%, based on the total weight of the slurry.

37. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry has a solids content of at least 2 wt%, 5 wt%, or 10 wt%, based on the total weight of the slurry.

38. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry has a solids content of at most 40 wt%, 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, or 10 wt%, based on the total weight of the slurry.

39. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry does not contain minerals and the slurry has a solids content of 2 wt% to 10 wt%.

40. The medical article or method of any one of the preceding exemplary embodiments, wherein the slurry comprises minerals and the slurry has a solids content of 10 wt% to 40 wt%.

41. The medical article or method of any of the preceding exemplary embodiments, wherein the slurry can be placed into a cylinder having two open ends at room temperature and the filled cylinder rotated on its wall such that the longitudinal axis of the cylinder faces horizontally and there will be substantially no leakage of slurry for at least 30 seconds, at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, or at least 1 hour.

42. The medical article or method of any one of the preceding exemplary embodiments, wherein the acid-soluble collagen is processed without the use of an enzyme.

43. The medical article or method of any one of the preceding exemplary embodiments, wherein the collagen fibers are natural collagen fibers.

44. The medical article or method of any one of the preceding exemplary embodiments, wherein the polymeric fibers have an average length of 1mm to 15mm.

45. The medical article or method of any one of the preceding exemplary embodiments, wherein the polymeric fibers have an average length of 0.5mm to 10mm.

46. The medical article or method of any one of the preceding exemplary embodiments, wherein the polymeric fibers have an average length of 1mm to 5mm.

47. The medical article or method of any one of the preceding exemplary embodiments, wherein the polymeric fibers have an average length of at least 0.5mm, at least 1mm, at least 2mm, at least 3mm, or at least 4mm.

48. The medical article or method of any one of the preceding exemplary embodiments, wherein the average length of the polymer fibers is at most 15mm, at most 12mm, at most 10mm, at most 9mm, at most 8mm, at most 7mm, at most 6mm, at most 5mm, or at most 4mm.

49. The method according to any one of the preceding exemplary embodiments, further comprising the step of centrifugally grinding the natural collagen fibers.

50. The medical article or method of any one of the preceding exemplary embodiments, further comprising the step of cutting the medical article into a desired shape.

51. The medical article or method of any of the preceding exemplary embodiments, further comprising the step of laser cutting the collagen sponge into a desired shape.

52. The medical article or method of any one of the preceding exemplary embodiments, further comprising the step of milling the surface of the medical article to a desired shape.

53. The medical article or method of any one of the preceding exemplary embodiments, wherein the medical article has a circular, elliptical, or polygonal footprint.

54. The medical article or method of any one of the preceding exemplary embodiments, wherein the medical article is a cylinder, an elliptical cylinder, or a general shape of a polyhedron.

55. The medical article or method of any one of the preceding exemplary embodiments, wherein the medical article is in the form of a three-dimensional shape comprising a reservoir capable of holding a liquid, the reservoir being defined by a sidewall and a recessed surface, wherein the sidewall comprises a plurality of cuts extending from a top surface thereof toward the recessed surface, wherein the plurality of cuts extend across a width of the sidewall.

56. The medical article or method of any one of the preceding exemplary embodiments, wherein the medical article is in a three-dimensional shape form comprising: the apparatus includes a base surface, a top surface, a recessed surface opposite the base surface, an outer surface extending between the base surface and the top surface, and an inner sidewall surface extending between the recessed surface and the top surface, wherein the three-dimensional shape includes a plurality of cuts extending from the top surface and through the inner sidewall surface and the outer surface.

57. The medical article or method of any one of the preceding exemplary embodiments, wherein the bottom surface or substrate of the medical article is a planar surface.

58. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall is a peripheral sidewall.

59. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall is annular in shape.

60. The medical article or method of any one of the preceding exemplary embodiments, wherein the top surface is an annular surface.

61. The medical article or method of any one of the preceding exemplary embodiments, wherein the outer surface and the base or bottom surface of the medical article intersect at an angle of less than 90 degrees.

62. The medical article or method of any one of the preceding exemplary embodiments, wherein the outer surface and the base or bottom surface of the medical article intersect at an angle of less than 80 degrees to 88 degrees.

63. The medical article or method of any one of the preceding exemplary embodiments, wherein the top surface of the sidewall meets the inner surface of the sidewall at an angle of about 90 degrees.

64. The medical article or method of any one of the preceding exemplary embodiments, wherein the top surface of the sidewall meets the outer surface of the sidewall at an angle of about 90 degrees.

65. The medical article or method of any one of the preceding exemplary embodiments, wherein the inner surface of the sidewall meets the recessed surface at an angle of about 90 degrees.

66. The medical article or method of any one of the preceding exemplary embodiments, wherein the inner surface of the sidewall meets the recessed surface at an angle greater than 90 degrees.

67. The medical article or method of any one of the preceding exemplary embodiments, wherein the recessed surface is planar.

68. The medical article or method of any one of the preceding exemplary embodiments, wherein the concave surface is curved.

69. The medical article or method of any one of the preceding exemplary embodiments, wherein the recessed surface is concave.

70. The medical article or method of any one of the preceding exemplary embodiments, wherein the concave surface is parabolic.

71. The method of any of the preceding exemplary embodiments, wherein the obstruction comprises a convex (convex) surface.

72. The medical article or method of any one of the preceding exemplary embodiments, wherein the outer surface comprises a first portion and a second portion, the first portion extending at an angle of less than 90 degrees relative to the base or bottom surface, and the second portion extending at an angle of about 90 degrees relative to the base or bottom surface.

73. The medical article or method of any one of the preceding exemplary embodiments, wherein the outer surface comprises a first portion and a second portion, the first portion beginning at an angle of less than 90 degrees with respect to the base or bottom surface from the first end, and the second portion ending at a top surface at an angle of about 90 degrees with respect to the base or bottom surface.

74. The medical article or method of any one of the preceding exemplary embodiments, wherein the outer surface comprises a first surface and a second surface, wherein the surfaces meet at an angle of less than 180 degrees.

75. The medical article or method of any one of the preceding exemplary embodiments, wherein the outer surface comprises a first surface and a second surface, wherein the surfaces meet at an angle of 160 degrees to 179 degrees.

76. The medical article or method of any of the preceding exemplary embodiments, wherein the inner sidewall surface comprises a first surface and a second surface, wherein the surfaces meet at an angle of less than 180 degrees.

77. The medical article or method of any of the preceding exemplary embodiments, wherein the inner sidewall surface comprises a first surface and a second surface, wherein the surfaces meet at an angle of 160 degrees to 179 degrees.

78. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall comprises a surface that meets the recessed surface at an angle greater than 90 degrees.

79. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall comprises a surface that meets the recessed surface at an angle of 91 degrees to 110 degrees.

80. The medical article or method of any one of the preceding exemplary embodiments, wherein the outer surface comprises a surface that meets the bottom surface at an angle of 70 degrees to 89 degrees.

81. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall comprises a cutout.

82. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall comprises two, three, four, five, six, seven, or eight incisions.

83. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall comprises two to eight incisions.

84. The medical article or method of any one of the preceding exemplary embodiments, wherein the incision has a square, rectangular, trapezoidal, partially elliptical, or partially circular cross-sectional shape.

85. The medical article or method of any one of the preceding exemplary embodiments, wherein the cut has a cube, rectangular prism, trapezoidal prism, partial sphere, or partial oval shape.

86. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall comprises a plurality of evenly spaced cuts.

87. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall comprises one or more cuts made up of surfaces intersecting each other at about 90 degrees.

88. The medical article or method of any one of the preceding exemplary embodiments, wherein the sidewall includes a cutout extending from the top surface of the sidewall in the direction of the recessed surface but not to the recessed surface.

89. The medical article or method of any of the preceding exemplary embodiments, wherein the size of the incision is indicative of a height of rehydration fluid that should be deposited in the reservoir in order to suitably rehydrate the medical article.

90. The medical article or method of any one of the preceding exemplary embodiments, wherein the medical article has a volume of 0.5 cubic centimeters to 15 cubic centimeters.

91. The medical article or method of any one of the preceding exemplary embodiments, wherein the medical article or slurry further comprises a bioactive agent.

92. The method or medical article of any one of the preceding exemplary embodiments, wherein the medical article or slurry further comprises bone morphogenic proteins, demineralized bone matrix, growth factors, or stem cells.

93. The medical article or method of any one of the preceding exemplary embodiments, further comprising a coating comprising a bioactive agent present on an outer surface of the medical article.

94. A medical article formed according to the method of any of the preceding exemplary embodiments.

95. A medical article formed according to the method of any of the preceding exemplary embodiments, wherein the medical article comprises at least one reservoir.

96. A method of treating a bone defect, the method comprising the steps of:

a. providing a medical article according to any of the preceding exemplary embodiments,

b. a liquid is placed in the reservoir and,

c. manipulating the medical article such that the liquid is absorbed into the medical article and rehydrated, thereby forming a putty,

d. the putty is inserted into the bone defect of the patient.

97. The method of treating a bone defect according to the foregoing exemplary embodiment, the method further comprising the steps of: placing the putty into a syringe, wherein the step of inserting the putty into a bone defect of a patient is performed by dispensing the putty into the bone defect via the syringe.

98. The medical article or method of any one of the preceding exemplary embodiments, wherein the medical article is a tissue repair device.

99. The medical article or method of any one of the preceding exemplary embodiments, wherein the medical article is a bone void filler or is suitable for filling a defect in bone.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Unless otherwise indicated, the terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"). Unless otherwise indicated herein, the description of ranges of values herein is intended only as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. While certain optional features are described as embodiments of the invention, this description is intended to include and specifically disclose all combinations of these embodiments, unless explicitly stated otherwise or physically impossible.

Claims (25)

1. A medical article comprising a sponge in the form of a three-dimensional shape comprising a reservoir capable of holding a liquid, the reservoir being defined by a sidewall and a recessed surface, wherein the sidewall comprises a plurality of cuts extending from a top surface thereof toward the recessed surface, wherein the plurality of cuts extend across a width of the sidewall.

2. The medical article of claim 1, wherein the sponge comprises natural polymer fibers.

3. The medical article according to any one of the preceding claims, wherein the sponge further comprises minerals and the minerals are present as particles having an average particle size of 0.05mm to 2 mm.

4. The medical article according to any one of the preceding claims, wherein the dry sponge comprises 50 to 95 wt% minerals and 5 to 50 wt% collagen, based on the total weight of the dry sponge.

5. The medical article according to any one of the preceding claims, wherein the sponge comprises acid-soluble collagen, collagen fibers, and mineral particles.

6. The medical article according to any one of the preceding claims, wherein the sponge comprises natural collagen fibers having an average fiber length of 0.5mm to 10 mm.

7. The medical article of any one of the preceding claims, wherein the medical article is a cylinder, an elliptical cylinder, or a general shape of a polyhedron.

8. The medical article of any one of the preceding claims, wherein the sidewall comprises two to eight cutouts.

9. The medical article of any one of the preceding claims, wherein the sidewall includes a cutout extending from the top surface of the sidewall in the direction of the recessed surface but not to the recessed surface.

10. The medical article of any one of the preceding claims, wherein the cutout has a square, rectangular, trapezoidal, partially elliptical, or partially circular cross-sectional shape.

11. The medical article of any one of the preceding claims, wherein the top surface of the sidewall meets an outer surface of the sidewall at an angle of about 90 degrees.

12. The medical article of any one of the preceding claims, wherein the top surface of the sidewall meets an inner surface of the sidewall at an angle of about 90 degrees.

13. The medical article of any one of the preceding claims, wherein the concave surface is concave.

14. The medical article according to any one of the preceding claims, wherein the medical article is a bone void filler or is suitable for filling defects in bone.

15. A method of forming a medical article comprising a sponge, the method comprising the steps of:

a. providing a mold, the mold comprising:

i. a tube comprising a first open end, a second open end and a wall extending therebetween, an

A stopper present in the tube, wherein the stopper is connected to the wall via an arm extending from the wall to the stopper,

b. A slurry is provided that includes water and,

c. forcing the slurry from the first open end through the tube to the second open end and past the obstruction to substantially fill the mold with slurry, an

d. Lyophilizing the slurry present in the mold, thereby forming a sponge comprising a reservoir.

16. The method of claim 15, wherein the slurry further comprises minerals and the minerals are present as particles having an average particle size of 0.05mm to 2 mm.

17. The method of claim 15 or 16, wherein the slurry further comprises a soluble biopolymer of natural or synthetic origin.

18. The method of any one of claims 15-17, wherein the dry sponge comprises 50 to 95 wt% minerals and 5 to 50 wt% collagen, based on the total weight of solids of the slurry.

19. The method of any one of claims 15-18, wherein the slurry further comprises acid-soluble collagen, collagen fibers, and mineral particles.

20. The method of any one of claims 15-19, wherein the slurry further comprises minerals and the slurry has a solids content of 10 wt% to 40 wt%.

21. The method of any one of claims 15-20, wherein the tube is cylindrical or elliptical cylinder shaped.

22. The method of any one of claims 15-21, wherein the mold comprises two to eight of the arms.

23. The method of any one of claims 15-22, wherein the obstruction comprises a convex surface.

24. A medical article formed by the method of any one of claims 15-23.

25. The medical article of claim 24, wherein the medical article is a bone void filler or is adapted to fill a defect in bone.