Hybrid biologic/synthetic porous extracellular matrix scaffolds

• US 7,914,808 B2
• Filed: 07/15/2002
• Issued: 03/29/2011
• Est. Priority Date: 07/16/2001
• Status: Active Grant

• Current Assignee: DePuy Synthes Products LLC (Johnson & Johnson)
• Original Assignee: Depuy Products Incorporated (Johnson & Johnson)
• Inventors: Melican, Mora C., Malaviya, Prasanna, Chun, Iksoo, Rezania, Alireza
• Primary Examiner(s): DRISCOLL, LORA E BARNHART
• Application Number:
  US10/195,341
• Publication Number:
  US 20030021827A1
• Time in Patent Office: 3,179 Days
• Field of Search: 424/423, 424/426, 623/11.11
• US Class Current: 424/423
• CPC Class Codes: A61B 17/0401 Suture anchors, buttons or pledgets, i.e. means for attaching sutures to bone, cartilage or soft tissue; Instruments for applying or removing suture anchors A61B17/0642 takes precedence; fixation devices for tendons or ligaments A61F2/0811
• CPC Class Codes: A61B 17/06166 Sutures suture materials A61L17/00; manufacture of artificial threads D01D; treatment of threads D06M
• CPC Class Codes: A61B 17/064 Surgical staples, i.e. penetrating the tissue
• CPC Class Codes: A61B 17/0642 for bones, e.g. for osteosynthesis or connecting tendon to bone
• CPC Class Codes: A61B 2017/00004 (bio)absorbable, (bio)resorbable or resorptive
• CPC Class Codes: A61B 2017/0475 using sutures having a slip knot
• CPC Class Codes: A61B 2017/06057 Double-armed sutures, i.e. sutures having a needle attached to each end
• CPC Class Codes: A61B 2017/0646 for insertion into cartillege, e.g. meniscus
• CPC Class Codes: A61F 2/0063 Implantable repair or support meshes, e.g. hernia meshes
• CPC Class Codes: A61F 2/08 Muscles; Tendons; Ligaments sutures A61B17/04
• CPC Class Codes: A61F 2/0811 Fixation devices for tendons or ligaments
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/30749 Fixation appliances for connecting prostheses to the body
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61F 2/3094 Designing or manufacturing processes
• CPC Class Codes: A61F 2/30965 Reinforcing the prosthesis by embedding particles or fibres during moulding or dipping
• CPC Class Codes: A61F 2/3872 Meniscus for implantation between the natural bone surfaces
• CPC Class Codes: A61F 2/442 Intervertebral or spinal discs, e.g. resilient non-disc-shaped intervertebral inflatable pockets A61F2/441; non-disc-shaped intervertebral fusion implants A61F2/4455
• CPC Class Codes: A61F 2002/2817 Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
• CPC Class Codes: A61F 2002/2839 Bone plugs or bone graft dowels
• CPC Class Codes: A61F 2002/30032 : differing in absorbability or resorbability, i.e. in absorption or resorption time
• CPC Class Codes: A61F 2002/30062 : (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30131 : horseshoe- or crescent- or C-shaped or U-shaped
• CPC Class Codes: A61F 2002/30153 : rectangular
• CPC Class Codes: A61F 2002/30199 : Three-dimensional shapes
• CPC Class Codes: A61F 2002/3021 : frustoconical
• CPC Class Codes: A61F 2002/30217 : hollow cones, e.g. tubular-like cones
• CPC Class Codes: A61F 2002/30224 : cylindrical
• CPC Class Codes: A61F 2002/30225 : Flat cylinders, i.e. discs
• CPC Class Codes: A61F 2002/30233 : Stepped cylinders, i.e. having discrete diameter changes
• CPC Class Codes: A61F 2002/30261 : parallelepipedal
• CPC Class Codes: A61F 2002/30281 : wedge-shaped
• CPC Class Codes: A61F 2002/30293 : Cylindrical body made by spirally rolling up a sheet or a strip around itself
• CPC Class Codes: A61F 2002/30294 : Conical or frustoconical body made by spirally rolling up a sheet or a strip around itself
• CPC Class Codes: A61F 2002/30429 : made by inserting a hook into a cooperating slot
• CPC Class Codes: A61F 2002/30604 : modular
• CPC Class Codes: A61F 2002/30677 : Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61F 2002/30751 : for attaching cartilage scaffolds to underlying bone
• CPC Class Codes: A61F 2002/30764 : Cartilage harvest sites
• CPC Class Codes: A61F 2002/30766 : Scaffolds for cartilage ingrowth and regeneration
• CPC Class Codes: A61F 2002/30785 : parallel
• CPC Class Codes: A61F 2002/30841 : Sharp anchoring protrusions for impaction into the bone, e.g. sharp pins, spikes
• CPC Class Codes: A61F 2002/30845 : with cutting edges
• CPC Class Codes: A61F 2002/30878 : with non-sharp protrusions, for instance contacting the bone for anchoring, e.g. keels, pegs, pins, posts, shanks, stems, struts
• CPC Class Codes: A61F 2002/30891 : Plurality of protrusions
• CPC Class Codes: A61F 2002/30892 : parallel
• CPC Class Codes: A61F 2002/30914 : Details of the mesh structure, e.g. disposition of the woven warp and weft wires
• CPC Class Codes: A61F 2002/30957 : using a positive or a negative model, e.g. moulds
• CPC Class Codes: A61F 2002/3096 : trimmed or cut to a customised size
• CPC Class Codes: A61F 2002/30971 : Laminates, i.e. layered products
• CPC Class Codes: A61F 2002/30975 : made of two halves
• CPC Class Codes: A61F 2210/0004 : bioabsorbable
• CPC Class Codes: A61F 2220/0025 : Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements
• CPC Class Codes: A61F 2230/0013 : Horseshoe-shaped, e.g. crescent-shaped, C-shaped, U-shaped
• CPC Class Codes: A61F 2230/0019 : rectangular
• CPC Class Codes: A61F 2230/0063 : Three-dimensional shapes
• CPC Class Codes: A61F 2230/0067 : conical
• CPC Class Codes: A61F 2230/0069 : cylindrical
• CPC Class Codes: A61F 2230/0082 : parallelepipedal
• CPC Class Codes: A61F 2230/0086 : Pyramidal, tetrahedral, or wedge-shaped
• CPC Class Codes: A61F 2230/0091 : helically-coiled or spirally-coiled, i.e. having a 2-D spiral cross-section
• CPC Class Codes: A61F 2240/001 : Designing or manufacturing processes
• CPC Class Codes: A61F 2240/004 : Using a positive or negative model, e.g. moulds
• CPC Class Codes: A61F 2250/003 : differing in adsorbability or resorbability, i.e. in adsorption or resorption time
• CPC Class Codes: A61F 2250/0063 : Nested prosthetic parts
• CPC Class Codes: A61F 2250/0067 : Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61F 2310/00365 : Proteins; Polypeptides; Degradation products thereof
• CPC Class Codes: A61L 2430/06 : for cartilage reconstruction, e.g. meniscus
• CPC Class Codes: A61L 27/18 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/3629 : Intestinal tissue, e.g. small intestinal submucosa
• CPC Class Codes: A61L 27/3633 : Extracellular matrix [ECM]
• CPC Class Codes: A61L 27/3683 : subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3691 : characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
• CPC Class Codes: A61L 27/56 : Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 31/005 : Ingredients of undetermined constitution or reaction products thereof
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

Methods of making a hybrid biologic/synthetic scaffold for repairing damaged or diseased tissue are provided. The methods include the step of suspending pieces of an extracellular matrix material in a liquid to form a slurry, and coating a synthetic mat with the slurry, or mixing or layering the slurry with a synthetic polymer solution. The liquid is subsequently driven off so as to form a foam. Porous implantable scaffolds fabricated by such a method are also disclosed.

Claims

1. A method of making an implantable scaffold for repairing or regenerating body tissue, the method comprising the steps of:

cutting a naturally occurring extracellular matrix in the presence of a liquid to produce a cohesive mass of intertwined strips, ribbons, or fibers;

contacting a synthetic polymer with the cohesive mass to make a composition comprising the cohesive mass and the polymer;

freezing the composition comprising the cohesive mass and the polymer to form a frozen composition, said frozen composition comprising crystals, and

driving off the crystals to form a foam.

2. The method of claim 1, further comprising the step of centrifuging the cohesive mass to compact the cohesive mass prior to the step of contacting the synthetic polymer with the cohesive mass.

3. The method of claim 1, wherein the naturally occurring extracellular matrix is selected from the group consisting of small intestinal submucosa, stomach submucosa, bladder submucosa, alimentary submucosa, respiratory submucosa, genital submucosa, and liver basement membrane.

4. The method of claim 1, wherein the synthetic polymer is formed as a mat, and said contacting step comprises coating the mat with the cohesive mass to form a coated mat, prior to the freezing step.

5. The method of claim 4, wherein the coating step comprises immersing the mat in the cohesive mass.

6. The method of claim 4, wherein the coating step includes placing the cohesive mass onto the mat and centrifuging the mat.

7. The method of claim 4, further comprising the step of driving a needle into the coated mat.

14. The method of claim 1, further comprising the step of crosslinking the components of the foam.

15. The method of claim 1, wherein the driving off step is performed by lyophilization of the frozen composition comprising the cohesive mass and the polymer.

16. The method of claim 1, further comprising the step of adding an exogenous biologically active agent.

17. The method of claim 16, wherein the biologically active agent is added prior to the freezing step.

18. The method of claim 16, wherein the biologically active agent is added after the step of driving off the crystals.

19. The method of claim 1, further comprising the step of shaping the foam.

20. The method of claim 1 wherein the naturally occurring extracellular matrix comprises small intestine submucosa.

21. The method of claim 20 wherein the strips, ribbons, or fibers are about 200 microns thick and 1-5 mm long.

8. A method of making an implantable scaffold comprising the steps of:

comminuting a naturally occurring extracellular matrix in a liquid to form ribbon-like pieces of the naturally-occurring extracellular matrix suspended in the liquid and intertwining said ribbon-like pieces of the naturally-occurring extracellular matrix by mixing to form a cohesive naturally occurring extracellular matrix;

contacting the cohesive naturally occurring extracellular matrix with synthetic polymers to form a composition comprising a cohesive naturally occurring extracellular matrix layer, a synthetic polymer layer and a transition zone comprising both the cohesive naturally occurring extracellular matrix and synthetic polymers;

freezing the composition to form a frozen composition, said frozen composition comprising crystals, and

driving off the crystals to form a foam.

11. The method of claim 8, wherein the naturally occurring extracellular matrix is selected from the group consisting of small intestine submucosa, stomach submucosa, bladder submucosa, alimentary submucosa, respiratory submucosa, genital submucosa, and liver basement membrane.

13. The method of claim 8, further comprising the step of allowing the cohesive naturally occurring extracellular matrix layer and the synthetic polymer layer to expand and mix with each other for a length of time prior to the freezing step to increase the width of the transition zone.

22. The method of claim 8 further comprising the step of centrifuging the cohesive naturally occurring extracellular matrix, removing the supernatant, and contacting the resulting compacted, cohesive naturally occurring extracellular matrix with the synthetic polymer-comprising composition.

24. The method of claim 8, further comprising the step of crosslinking the components of the foam.

26. The method of claim 8, wherein the driving off step is performed by lyophilization of the frozen composition.

27. The method of claim 8, further comprising the step of adding an exogenous biologically active agent.

9. A method of making an implantable scaffold comprising the steps of:

cutting a naturally occurring extracellular matrix in the presence of a liquid to produce a cohesive mass of intertwined strips, ribbons, or fibers;

coating a synthetic polymer mat with the cohesive mass;

freezing the coated mat to form a frozen composition, said frozen composition comprising crystals, and

driving off the crystals to form a foam coated mat.

10. The method of claim 9, further comprising the steps of:

mixing a composition comprising synthetic polymers with the cohesive mass; and

coating the synthetic mat with the mixture.

12. The method of claim 9, wherein the naturally occurring extracellular matrix is selected from the group consisting of small intestine submucosa, stomach submucosa, bladder submucosa, alimentary submucosa, respiratory submucosa, genital submucosa, and liver basement membrane.

23. The method of claim 9 further comprising the step of centrifuging the cohesive mass, removing the supernatant, and mixing the resulting compacted, cohesive mass with the synthetic polymer mat.

25. The method of claim 9, further comprising the step of crosslinking the components of the foam.

28. A method of making an implantable scaffold for repairing or regenerating body tissue, the method comprising the steps of:

i) obtaining small intestine submucosa from an animal;

ii) placing said small intestine submucosa into water;

iii) cutting said small intestine submucosa into strips or fibers, wherein said strips or fibers intertwine;

iv) contacting a synthetic polymer with said intertwined strips of small intestine submucosa to produce a composition comprising said synthetic polymer and said intertwined strips of small intestine submucosa; and

v) freeze-drying said composition to yield an implantable scaffold.