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WO2000047114A1 - Systeme d'apport de proteines osseuses morphogenetiques par injection de collagene - Google Patents

Systeme d'apport de proteines osseuses morphogenetiques par injection de collagene Download PDF

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Publication number
WO2000047114A1
WO2000047114A1 PCT/US2000/003151 US0003151W WO0047114A1 WO 2000047114 A1 WO2000047114 A1 WO 2000047114A1 US 0003151 W US0003151 W US 0003151W WO 0047114 A1 WO0047114 A1 WO 0047114A1
Authority
WO
WIPO (PCT)
Prior art keywords
bmp
collagen
fibrillar
solution
bone
Prior art date
Application number
PCT/US2000/003151
Other languages
English (en)
Inventor
Dale P. Devore
Original Assignee
Collagenesis, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Collagenesis, Inc. filed Critical Collagenesis, Inc.
Priority to AU29847/00A priority Critical patent/AU2984700A/en
Publication of WO2000047114A1 publication Critical patent/WO2000047114A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor

Definitions

  • this invention relates to a delivery system for bone morphogenic proteins.
  • Bone is a living, dynamic tissue with substantial capacity for regeneration. Through the tightly-controlled, ongoing processes of formation and reso ⁇ tion, bone is involved in the regulation of serum calcium, is able to remodel in order to respond to changes in physical stress placed upon it, and is able to repair both micro fractures and substantial fractures within its structure. These processes are controlled, at least in part, by the large number of growth factors present in the bone matrix. These factors include basic and acidic fibroblast growth factor, insulin-like growth factors I and II, the superfamily of transforming growth factors beta (TGF ⁇ ), platelet derived growth factors, and bone mo ⁇ hogenic proteins.
  • TGF ⁇ transforming growth factors beta
  • the bone mo ⁇ hogenic proteins are now known to include a large family of proteins within the TFG ⁇ superfamily of growth and differentiation factors.
  • Members of the BMP family have been determined to be key signaling molecules in embryogenesis, in species ranging from Drosophila to humans. They are involved in delivering positional information as well as the development of hard tissues (bones and teeth) and soft tissues.
  • BMPs When implanted into adult animals, several of the BMPs have been shown to initiate the complex cellular process resulting in the induction of bone through both the endochondral and intramembranous bone formation pathways.
  • the invention features a method for delivering a bone mo ⁇ hogenic protein to a tissue site, the method involving: (a) combining the bone mo ⁇ hogenic protein (BMP) with a soluble collagen; and (b) administering the BMP-collagen solution to the tissue site, whereby, upon contact with the tissue, the collagen solution is converted to a collagen gel.
  • BMP bone mo ⁇ hogenic protein
  • the BMP-collagen solution is administered by injection; the tissue site is bone or cartilage; the site has a defect; the defect is treated by BMP delivery; the collagen solution, upon administration to the tissue, is converted to a collagen gel within 180 seconds, more preferably, within 120 seconds, and, most preferably, within 90 seconds: the soluble collagen includes a fibrillar component and forms a fibrillar matrix: the fibrillar component is at a concentration of between 0.01-2.0%, more preferably, 0.1 -0.8% (fibrillar collagen solids (w/v)); the BMP-collagen solution is at approximately pH 5.5-7.5, preferably, approximately 6.0-6.5; and the bone mo ⁇ hogenic protein is selected from the TGF ⁇ superfamily, e.g., BMP-1 , BMP-2 (BMP-2A), BMP-3 (osteogenin), BMP-4 (BMP-2B), BMP-5. BMP-6, BMP-7, osteoinductive factor (OIF), BMP-8, BMP-9, BMP
  • the invention features a bone mo ⁇ hogenic protein (BMP)-collagen solution, whereby, upon administration to a tissue, the solution is converted to a collagen gel.
  • BMP bone mo ⁇ hogenic protein
  • this BMP-collagen solution is injectable; the BMP-collagen solution, upon administration to a tissue, is converted to a collagen gel within 180 seconds, more preferably, within 120 seconds, and, most preferably, within 90 seconds; the BMP-collagen solution includes a fibrillar component and forms a fibrillar matrix; the fibrillar component is at a concentration of 0.01 -2.0%, more preferably, 0.1-0.8% (fibrillar collagen solids (w/v)); the BMP-collagen solution is at approximately pH 5.5-7.5, more preferably, at approximately pH 6.0-6.5; and the bone mo ⁇ hogenic protein is selected from the TGF ⁇ superfamily, e.g., BMP-1 , BMP-2 (BMP-2 A), BMP-3 (osteogenin), BMP-4 (BMP-2B), BMP-5, BMP-6, BMP-7, osteoinductive factor (OIF), BMP-8, BMP-9, BMP- 10, BMP- 12, BMP- 13, and BMP- 14.
  • BMP-1 B
  • tissue is meant an aggregation of similarly specialized cells in an organism, preferably, mammalian, and, most preferably, human, where the cells are exposed to the organism's extracellular fluid, and are united in performance of a function within an organism.
  • fibrillar component is meant an insoluble fibrillar collagen component wherein the collagen molecules interact in a quarter-stagger array to form microfibrils which themselves aggregate by side-to-side and end-to-end association to form stabilized collagen fibrils.
  • the fibrillar component exhibits a collagen solid content ranging from about 0.1 -2.0% (w/v) fibrillar collagen solids.
  • fibrillar collagen solids the dry collagen solid content of the fibrillar component in terms of percent fibrillar solids.
  • the collagen solids Prior to addition to a soluble collagen formulation, the collagen solids are suspended in solution at a concentration ranging from 10-100 mg/ml, preferably 40 mg/ml. The collagen solid suspension is then added to the soluble collagen formulation for a final collagen solid concentration of 0.1 -2.0%, or 1 -20 mg/ml.
  • the collagen delivery systems described herein are biocompatible, readily available, and stable in solution at neutral pH. These properties allow for the homogeneous dispersion of active BMP peptides, injectable administration of these peptides through a fine gauge needle (for example, a 30 gauge needle), sufficient density to fill a bone defect and to remain in place until gelation and fibril formation, and substantial BMP delivery for the maintenance of the active peptide in the bone matrix for a period of time sufficient to promote healing.
  • a fine gauge needle for example, a 30 gauge needle
  • FIGURE 1 is a graph demonstrating recombinant human BMP-2 retention following injection in combination with either the presently-described rapidly polymerizing collagen containing a 20% fibrillar collagen component, buffer, or a collagen sponge.
  • an injectable deliver ⁇ ' system for BMPs which involves an initially soluble collagen which is capable of rapid polymerization.
  • the low viscosity of the initial collagen solution allows homogeneous mixing of the introduced BMP and administration to a site by injection.
  • the rapid polymerization characteristic allows for targeted delivery of the peptide to specific tissue sites and in concentrations which may be readily controlled through the choice of BMP concentration in the soluble collagen mixture.
  • any collagen which exhibits the properties of an initially soluble state followed by rapid polymerization may be used in the invention. Because this delivery system is optimally designed for use in mammalian systems, rapid polymerization preferably occurs at temperatures and pH's which approximate the physiological conditions of the recipient mammal. For humans, this collagen preferably polymerizes in a range of about 36°-39°C and at a pH of about 6.5-7.5.
  • collagens for use in the invention are described in DeVore & Eiferman (U.S. Patent No. 5,492,135.) These collagens are initially soluble in form and, upon exposure to physiological fluids, undergo rapid polymerization. Such collagen solutions have been prepared at concentrations ranging from 10 mg/ml to over 70 mg/ml and at pH's ranging from about 6.0-8.0.
  • Fibrillar collagen may be reconstituted from animal sources, such as bovine hide, using methods described, for example, in Borel and Randoux, Frontiers in Matrix Biology, Vol. 10, pages 1-58, In Methods of Connective Tissue Research, Eds. Robert, Moczar, and Moczar, S. Karger, Basel, 1985. Fibrillar collagen may also be prepared from human or animal tissue sources using the method of Kelman and DeVore (U.S. Patent Nos. 4,969,912 and 5,322,802.) Concentrations of the fibrillar collagen component may range from about 0.01 -2.0% (collagen solids (w/v)).
  • the injectable collagen systems described herein may be used to deliver any bone mo ⁇ hogenic protein selected from the TGF ⁇ superfamily, including, without limitation, BMP- 1 , BMP-2 (BMP-2A), BMP-3 (osteogenin). BMP-4 (BMP-2B), BMP-5. BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP- 1 1 , BMP-12, BMP- 13, BMP-14 and osteoinductive factor (OIF).
  • the bone mo ⁇ hogenic protein is BMP-2.
  • the protein is added to the collagen solution to a desired concentration, and the solution is administered to the appropriate tissue site.
  • combinations of two or more BMPs may be administered simultaneously, or the BMP may be combined with other compounds which encourage bone formation, for example, hydroxyapatite, calcium phosphate, or other non-collagen materials such as coral powder.
  • the collagen-BMP solution is administered to a site, for example, the site of a bone or collagen defect by syringe injection or surgical placement.
  • the injectable collagen-BMP delivery system described herein is ideally suited to the treatment and repair of bone defects (for example, injury, fracture, or non-union fracture) or cartilage defects or injury.
  • the collagen-BMP preparation can also be applied to increase bone density in the treatment of osteoporosis.
  • BMP-2 recombinant human BMP-2 was used. Experiments were conducted to determine whether the addition of BMP in buffer (pH 4.5) would impede gelation or fibril formation. BMP was added to collagen at a 1 : 1 ratio, mixed using two syringes attached by a syringe adaptor, and then injected into a 0.8% saline solution. The still viscous mixture sank to the bottom of the solution. Gelation and fibril formation occurred within 1 minute of introduction into the saline.
  • the 20% fibrillar collagen formulation had greater BMP retention at the implantation site than did the 10% fibrillar formulation. Indeed, the 20% fibrillar collagen formulation retained 60% of the BMP retained using a surgically-implanted sponge (a standard treatment) and 150% of that retained following BMP-buffer injections. Comparative retention was consistent for up to nearly 200 hours post- implantation ( Figure 1).
  • Rapidly polymerizing collagen formulations containing 20% fibrillar bovine collagen matrix and BMP (mixed with ,25 I-BMP) were also injected into bone-groove defects in rabbit forelimb long bones (80 ⁇ g BMP/200 ⁇ l aliquot).
  • Surgically-implanted sponges containing BMP and injections of BMP in buffer were used as non-collagen controls.
  • Animals were examined radiographically at 3, 24, 47, 72, 100, 170, and 190 hours post-treatment, as well as at 2, 3, and 4 weeks post-treatment. At 4 weeks, the implant sites and surrounding bone were removed for histological examination.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé d'apport d'une protéine osseuse morphogénétique à un tissu consistant : (a) à combiner la protéine osseuse morphogénétique (BMP) avec un collagène soluble ; et (b) à administrer cette solution au tissu, au contact duquel cette solution se transforme en collagène gélifié. Cette invention concerne également l'utilisation de ce procédé pour traiter les anomalies osseuses ou celles des cartilages. De plus, cette invention propose des solutions BMP-collagènes utiles à cet effet.
PCT/US2000/003151 1999-02-12 2000-02-07 Systeme d'apport de proteines osseuses morphogenetiques par injection de collagene WO2000047114A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29847/00A AU2984700A (en) 1999-02-12 2000-02-07 Injectable collagen-based delivery system for bone morphogenic proteins

Applications Claiming Priority (2)

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US11993999P 1999-02-12 1999-02-12
US60/119,939 1999-02-12

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WO2000047114A1 true WO2000047114A1 (fr) 2000-08-17

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051449A2 (fr) * 2000-12-22 2002-07-04 Sulzer Biologics Inc. Composition et methode de croissance et de reparation osseuse
US20030143207A1 (en) * 2001-10-18 2003-07-31 Livesey Stephen A. Remodeling of tissues and organ
WO2003094835A2 (fr) 2002-05-09 2003-11-20 Prochon Biotech Ltd. Variantes de fgf et leurs procedes d'utilisation
WO2006007780A1 (fr) * 2004-07-22 2006-01-26 Fang Xu Matiere pour reparation d'os sous forme de gelatine injectable et son procede de preparation
WO2008079672A2 (fr) * 2006-12-19 2008-07-03 Warsaw Orthopedic, Inc Compositions de vecteur fluide et procédés d'utilisation
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
USRE42208E1 (en) 2003-04-29 2011-03-08 Musculoskeletal Transplant Foundation Glue for cartilage repair
US8292968B2 (en) 2004-10-12 2012-10-23 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
EP2716299A2 (fr) * 2011-06-03 2014-04-09 Chonnam National University Hospital Peptide bfp4 favorisant la formation osseuse ou la vasculogenèse, et son application
US8906110B2 (en) 2007-01-24 2014-12-09 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US9089523B2 (en) 2011-07-28 2015-07-28 Lifecell Corporation Natural tissue scaffolds as tissue fillers
US9271821B2 (en) 2012-01-24 2016-03-01 Lifecell Corporation Elongated tissue matrices
US9370536B2 (en) 2012-09-26 2016-06-21 Lifecell Corporation Processed adipose tissue
US9375017B2 (en) 2009-01-02 2016-06-28 Lifecell Corporation Method for debristling animal skin
US9375513B2 (en) 2011-04-14 2016-06-28 Lifecell Corporation Regenerative materials
US9532863B2 (en) 2011-12-20 2017-01-03 Lifecell Corporation Sheet tissue products
US9549805B2 (en) 2011-12-20 2017-01-24 Lifecell Corporation Flowable tissue products
US9687590B2 (en) 2007-07-03 2017-06-27 Histogenics Corporation Double-structured tissue implant and a method for preparation and use thereof
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
US9782436B2 (en) 2012-04-24 2017-10-10 Lifecell Corporation Flowable tissue matrices
US9993326B2 (en) 2007-07-03 2018-06-12 Histogenics Corporation Method for use of a double-structured tissue implant for treatment of tissue defects
US9999637B2 (en) 2012-04-24 2018-06-19 Lifecell Corporation Functionalized tissue matrices
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
US10111981B2 (en) 2013-03-04 2018-10-30 Dermelle, Llc Injectable in situ polymerizable collagen composition
US10821205B2 (en) 2017-10-18 2020-11-03 Lifecell Corporation Adipose tissue products and methods of production
US11090338B2 (en) 2012-07-13 2021-08-17 Lifecell Corporation Methods for improved treatment of adipose tissue
US11123375B2 (en) 2017-10-18 2021-09-21 Lifecell Corporation Methods of treating tissue voids following removal of implantable infusion ports using adipose tissue products
US11246994B2 (en) 2017-10-19 2022-02-15 Lifecell Corporation Methods for introduction of flowable acellular tissue matrix products into a hand
US11633521B2 (en) 2019-05-30 2023-04-25 Lifecell Corporation Biologic breast implant
US11826488B2 (en) 2017-10-19 2023-11-28 Lifecell Corporation Flowable acellular tissue matrix products and methods of production

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Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051449A2 (fr) * 2000-12-22 2002-07-04 Sulzer Biologics Inc. Composition et methode de croissance et de reparation osseuse
WO2002051449A3 (fr) * 2000-12-22 2002-09-06 Sulzer Biolog Inc Composition et methode de croissance et de reparation osseuse
US8690874B2 (en) 2000-12-22 2014-04-08 Zimmer Orthobiologics, Inc. Composition and process for bone growth and repair
JP2004520106A (ja) * 2000-12-22 2004-07-08 サルザー バイオロジクス インコーポレイテッド 骨の成長および修復のための組成物ならびに方法
US20030143207A1 (en) * 2001-10-18 2003-07-31 Livesey Stephen A. Remodeling of tissues and organ
US7563769B2 (en) 2002-05-09 2009-07-21 ProChon Biotech, Ltd. FGF variants and methods for use thereof
US8916522B2 (en) 2002-05-09 2014-12-23 Prochon Biotech Ltd. FGF-9 variants and methods of use thereof
US9487568B2 (en) 2002-05-09 2016-11-08 Prochon Biotech Ltd. FGF-2 variants and methods of use thereof
WO2003094835A2 (fr) 2002-05-09 2003-11-20 Prochon Biotech Ltd. Variantes de fgf et leurs procedes d'utilisation
US8609823B2 (en) 2002-05-09 2013-12-17 ProChon Biotech, Ltd. FGF-9 variants and methods for use thereof
US8119783B2 (en) 2002-05-09 2012-02-21 Prochon Biotech Ltd. FGF variants and methods for use thereof
USRE42208E1 (en) 2003-04-29 2011-03-08 Musculoskeletal Transplant Foundation Glue for cartilage repair
USRE43258E1 (en) 2003-04-29 2012-03-20 Musculoskeletal Transplant Foundation Glue for cartilage repair
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
US8221500B2 (en) 2003-05-16 2012-07-17 Musculoskeletal Transplant Foundation Cartilage allograft plug
WO2006007780A1 (fr) * 2004-07-22 2006-01-26 Fang Xu Matiere pour reparation d'os sous forme de gelatine injectable et son procede de preparation
US8292968B2 (en) 2004-10-12 2012-10-23 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
WO2008079672A3 (fr) * 2006-12-19 2008-12-24 Warsaw Orthopedic Inc Compositions de vecteur fluide et procédés d'utilisation
US8048857B2 (en) 2006-12-19 2011-11-01 Warsaw Orthopedic, Inc. Flowable carrier compositions and methods of use
WO2008079672A2 (fr) * 2006-12-19 2008-07-03 Warsaw Orthopedic, Inc Compositions de vecteur fluide et procédés d'utilisation
US8906110B2 (en) 2007-01-24 2014-12-09 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
US10842610B2 (en) 2007-07-03 2020-11-24 Histogenics Corporation Method for use of a double-structured tissue implant for treatment of tissue defects
US9993326B2 (en) 2007-07-03 2018-06-12 Histogenics Corporation Method for use of a double-structured tissue implant for treatment of tissue defects
US9687590B2 (en) 2007-07-03 2017-06-27 Histogenics Corporation Double-structured tissue implant and a method for preparation and use thereof
US9375017B2 (en) 2009-01-02 2016-06-28 Lifecell Corporation Method for debristling animal skin
US9375513B2 (en) 2011-04-14 2016-06-28 Lifecell Corporation Regenerative materials
US10828391B2 (en) 2011-04-14 2020-11-10 Lifecell Corporation Regenerative materials
US9238055B2 (en) 2011-06-03 2016-01-19 Chonnam National University Hospital Peptide bone forming peptide 4 for promoting osteogenesis or vascularization and use thereof
EP2716299A4 (fr) * 2011-06-03 2014-12-24 Chonnam Nat University Hospital Peptide bfp4 favorisant la formation osseuse ou la vasculogenèse, et son application
EP2716299A2 (fr) * 2011-06-03 2014-04-09 Chonnam National University Hospital Peptide bfp4 favorisant la formation osseuse ou la vasculogenèse, et son application
US9089523B2 (en) 2011-07-28 2015-07-28 Lifecell Corporation Natural tissue scaffolds as tissue fillers
US9504770B2 (en) 2011-07-28 2016-11-29 Lifecell Corporation Natural tissue scaffolds as tissue fillers
US10092677B2 (en) 2011-07-28 2018-10-09 Lifecell Corporation Natural tissue scaffolds as tissue fillers
US10610615B2 (en) 2011-07-28 2020-04-07 Lifecell Corporation Natural tissue scaffolds as tissue fillers
US9549805B2 (en) 2011-12-20 2017-01-24 Lifecell Corporation Flowable tissue products
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US10722339B2 (en) 2011-12-20 2020-07-28 Lifecell Corporation Flowable tissue products
US10327884B2 (en) 2012-01-24 2019-06-25 Lifecell Corporation Elongated tissue matrices
US9271821B2 (en) 2012-01-24 2016-03-01 Lifecell Corporation Elongated tissue matrices
US9782436B2 (en) 2012-04-24 2017-10-10 Lifecell Corporation Flowable tissue matrices
US10314861B2 (en) 2012-04-24 2019-06-11 Lifecell Corporation Flowable tissue matrices
US9999637B2 (en) 2012-04-24 2018-06-19 Lifecell Corporation Functionalized tissue matrices
US10953044B2 (en) 2012-04-24 2021-03-23 Lifecell Corporation Functionalized tissue matrices
US11090338B2 (en) 2012-07-13 2021-08-17 Lifecell Corporation Methods for improved treatment of adipose tissue
US10709810B2 (en) 2012-09-26 2020-07-14 Lifecell Corporation Processed adipose tissue
US9370536B2 (en) 2012-09-26 2016-06-21 Lifecell Corporation Processed adipose tissue
US10111981B2 (en) 2013-03-04 2018-10-30 Dermelle, Llc Injectable in situ polymerizable collagen composition
US11235089B2 (en) 2013-03-04 2022-02-01 Shanghai Haohai Biological Technology Co., Ltd. Injectable in situ polymerizable collagen composition
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
US11555172B2 (en) 2014-12-02 2023-01-17 Ocugen, Inc. Cell and tissue culture container
US11123375B2 (en) 2017-10-18 2021-09-21 Lifecell Corporation Methods of treating tissue voids following removal of implantable infusion ports using adipose tissue products
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