WO1991017777A2 - Compositions de verre bioactives injectables et procede de reconstitution de tissus - Google Patents

Compositions de verre bioactives injectables et procede de reconstitution de tissus Download PDF

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Publication number
WO1991017777A2
WO1991017777A2 PCT/US1991/003596 US9103596W WO9117777A2 WO 1991017777 A2 WO1991017777 A2 WO 1991017777A2 US 9103596 W US9103596 W US 9103596W WO 9117777 A2 WO9117777 A2 WO 9117777A2
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WIPO (PCT)
Prior art keywords
glass
composition
bio
tissue
anatomic structure
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Application number
PCT/US1991/003596
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English (en)
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WO1991017777A3 (fr
Inventor
Dixon R. Walker
June Wilson Hench
Marc Ramer
Larry L. Hench
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University Of Florida
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Publication of WO1991017777A2 publication Critical patent/WO1991017777A2/fr
Publication of WO1991017777A3 publication Critical patent/WO1991017777A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
    • C03C4/00—Compositions for glass with special properties
    • C03C4/0007—Compositions for glass with special properties for biologically-compatible glass
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0084—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions

Definitions

  • the present invention relates to novel injectable bio- active glass compositions for the repair of hard bone or soft tissue of human and non-human animals.
  • Teflon particles have been introduced into the vocal cord and more recently into periureteral and periurethral tissues with mixed results. Disadvantages associated with this procedure include long-term progressive foreign-body reactions and migration and distant embolism associated with very small particles. Considerable research has been conducted to discover substitutes for Teflon and other conventionally employed artificial materials.
  • Urinary incontinence is a common accompaniment to diseases such as spina bifida and exstrophy of the bladder.
  • the reasons for the incontinence are multifactorial and include hyperactive bladder pressure, small-capacity bladder and decreased urethral resistance.
  • the preferred method of management is to place the patient in urinary retention and empty the bladder with clean inter-mittent catheterization. This has become the hallmark of urologic management in a large percentage of patients with spina bifida. Successful management of such patients requires an adequate bladder capacity, low intravesical pressure and a normal-to-high urethral resistance.
  • Urethral resistance can be increased by bladder neckplasty or a urethral sling procedure, both of which are open operations. Urethral resistance can also be increased by the periurethral injection of Teflon or collagen. Teflon has been used for fifteen years and does not have the permanent effect of increasing the urethral resistance. It has the unacceptable side effects in experimental animals of causing granulomas. Although clinically Teflon has been well tolerated, there have been reports of pulmonary granulomas in humans. The search for other injectable substances has resulted in the use of glutaraldehyde cross-linked bovine collagen which has been shown to increase urethral resistance. Unfortunately, experience has shown that collagen tends to break down over a period of months or years, resulting in a recurrence of incontinence.
  • Bio-active glasses have been utilized as bone replacement materials in a variety of reconstructive surgical techniques. These glasses have been shown to develop a strong bond with hard tissue due to a series of ion-exchange reactions between the implant surface and body fluids that result in the formation of a biologically active calcium phosphate film at the implant tissue interface [Hench et al., J. Biomed. Mater. Res... Vol. 5, pp. 117-141 (1971), and Hench et al., J. Biomed. Mater. Res.. Vol. 7, pp. 25-42 (1973)]. Bio-active glasses have also been shown to form firm bonds with soft tissue [Wilson et al., J. Biomed. Mater. Res.. Vol. 15, pp.
  • Certain bio-active and bio-compatible glasses and glass- ceramics i.e., those described in U.S. Patent Nos. 4,159,358; 4,234,972; 4,103,002; 4,189,325; 4,171,544; 4,775,646 and 4,851,046) have been shown to develop a unique, strongly adherent, chemical bond with hard-bone tissue due to the influence on hydroxyapatite of the biologically active calcium phosphate film generated in situ by ion-exchange reactions between the glass or glass-ceramic surface and body fluids. This influence results in a strong fixation of the glass or glass-ceramic to the bone surface.
  • a pharmaceutically acceptable fluid composition capable of injection via a surgical needle into a human or non-human animal and particularly adapted for the repair, replacement, reconfiguration, reconstruction or augmentation of selected hard bone and/or soft tissue anatomic structures therein comprising a homogeneous suspension in an aqueous solution of hyaluronic acid, salt or pharmaceutically acceptable derivative thereof (HA) having an average molecular weight of at least about 1 x 10 6 of at least one particulate bacteriostatic, bio-active and bio-compatible glass composition, the glass composition being one which:
  • the particulate glass has a particle size preferably from 355 ⁇ m to lOO ⁇ m;
  • the aqueous solution has a concentration of HA and the ratio of particulate glass to the aqueous solution in the suspension is such that the fluid composition remains homogeneous under pressures encountered during the injection and, following injection, the HA is bioresorbed by the animal and the particulate glass remains at the selected anatomic structures and bonds uniformly throughout the particulate surfaces thereof with the hard bond and/or soft tissue at the anatomic structures to provide anatomic integrity thereto without migration thereof or extrusion through adjacent tissue.
  • the invention further provides a method for the repair, replacement, reconstruction, reconfiguration or augmentation of a selected hard bone and/or soft tissue anatomic structure of a human or non-human animal comprising injecting into the anatomic structure the above-described composition.
  • Fig. 1 graphically depicts the spreading rates of varying HA compositions according to the invention.
  • Fig. 2 depicts a syringe and surgical needle system for delivery of the composition of the invention.
  • Fig. 3 graphically depicts injection force as a function of syringe volume for a single HA composition, the ratios of bio-active glass particulate/vehicle being between 0.32 and 0.4.
  • Fig. 4 is a ternary compositional boundary diagram of Si0 2 -CaO-Na 2 0 glasses.
  • Region A bounds those compositions which are bone-bonding glass formers. Ceravital ⁇ ** which is known to bond to bone tissue, but not to soft tissue, is located within Region A.
  • Region B comprises those compositions which are neither bone- nor soft-tissue bonding glass formers.
  • Region C defines those compositions which form glasses that dissolve in vivo when implanted in the body.
  • Region D defines bone-bonding non-glass formers.
  • Region E defines the compositions within Region A which form glasses capable of bonding to bone and forming acceptable thin cellular collagen bonds with soft tissue.
  • fluid as used herein is intended to include any flowable and injectable liquid composition, including highly viscous compositions sometimes referred to as "pastes.”
  • Hyaluronic acid, salt or other derivative thereof is intended to include hyaluronic acid, as well as salts or other derivatives naturally present in the human or non-human animal (e.g., in the vitreous humor, synovial fluid, etc.).
  • HA is employed to refer to hyaluronic acid, as well as suitable salts and/or derivatives thereof.
  • “Pharmaceutically acceptable” is intended to include any material which is compatible with the other ingredients of the composition, which are not deleterious to the recipient thereof, have the intended function and are capable of administration to its recipient in the intended manner.
  • HA hydroxyasemiconductor
  • HA fractions which are sterile, non- pyrogenic, non-antigenic and non-inflammatory as those terms are normally and conventionally employed in the art.
  • compositions and formulations of the invention may be presented in "unit dosage form" which is intended to include all amounts, ratios, concentrations, etc., of the composition effective to achieve the desired result or condition. It will be appreciated by those skilled in the art that dosages and dosage rates are adjusted according to the species of animal treated, magnitude of desired response and other factors routinely taken into consideration in establishing dose rates. They may be formulated by any of the methods described above or by any of the methods well known in the art of pharmacy for forming suspensions of solids in liquids.
  • surgical needle includes any needle adapted for delivery of the fluid compositions of the invention after injection into a selected anatomical structure. Typical such needles are used in conjunction with syringes utilizing a plunger to pressurize and deliver the composition to the intended site.
  • anatomic structure refers to any site or locus within the human or non-human animal, composed of hard bone and/or soft tissue, which requires repair, reconstruction, augmentation, replacement or reconfiguration to restore to transform it to a desired new configuration or state.
  • Exemplary of such anatomic structures treatable according to the method of the invention include vocal cords, periurethral tissue, periureteral tissue, maxilla, mandible, temporomandibular joint, chin, zygomatic arch, nose, ear, tooth root canal, tooth pulp caps, dental restoration, defects in bone, vertebral spaces, articulating joints, and subcutaneous and intradermal soft tissues.
  • anatomic integrity refers to the desired size, shape or configuration of a particular anatomic structure after bonding therewith of the particulate glass phase of the composition of the invention.
  • homogeneous as used herein is intended to include all compositions (l) not subject to preferential extrusion of one or more of the components when injected into the patient or animal and (2) not subject to segregation of one or more of the components of the mixture when allowed to stand for long periods of time.
  • bio-active and bio- compatible glasses having the following weight percent compositions give satisfactory results when utilized as the particulate glass component of the invention.
  • the thin (1-3 fibers) collagen bond and capsule formed after implantation of the glass composition according to the invention do not thicken with time.
  • the devices of the prior art usually fail because the included material and associated tissue response disappears with time as the material (for example, Teflon particles, hydroxyapatite particles, glass beads) is not bonded to and thus retained by the host tissues. Migration from the site removes the desired effect of tissue augmentation and provides additional hazard due to migration to other tissues with the potential for catastrophic embolism.
  • the particulate glass is preferably prepared according to the following method: the raw materials are mixed in a Nalgene container on a ball mill for four hours. The mix is then melted in a platinum crucible at 1350°C and homogenized for 24 hours. The molten glass is poured into distilled-deionized water to produce a glass frit, the frit is ground in a mortar and pestle and passed through ASTM sieves to produce the required particle size range.
  • the primary variables affecting the rheology of the bio- active compositions of the invention and the ability to inject through typical 16-18 gauge needles are: maximum particle size, range of particle sizes, ratio of the weight of glass particles to the weight of hyaluronic acid solution, and percentage of hyaluronic acid in solution.
  • Particles larger than 45 mesh ASTM Standard (355 ⁇ m) cannot be injected through a 16 gauge needle without unduly decreasing the volume of glass powder in the paste by a significant amount. Since the objective is to deliver as large a quantity of particles per injection as possible, the practical upper limit in particle size is about 355 ⁇ m.
  • Particles smaller than lOO ⁇ m are subject to macrophage attack in vivo. Since the objective is to retain the maximum number of particles in the tissues per injection, this establishes the lower limit of particle size at about lOO ⁇ m.
  • polymer for the injectable composition requires meeting three criteria: (1) the polymer must be bioresorbable with no negative biological responses, i.e., it must be metabolized relatively quickly and with no deleterious effects; (2) the rheological properties must be such that a relatively small quantity when mixed with a large volume of glass particulate will create a solution with a paste-like consistency which can be extruded through a needle; and (3) the viscosity/shear properties of the polymer must not lead to preferential extrusion or segregation of the polymer during injection.
  • Hyaluronic acid as well as its pharmaceutically acceptable salts and derivatives, meet each of the three criteria above.
  • Balazs et al. Proc. 5th Annual Conf. Biotechn. CMC Corp., pp. 1-8, 1988
  • the rate of removal of HA from the anterior chamber of the eye is only 1-2 days half-life and removal from blood is only 2-5 minutes half-life.
  • the removal is via the liver endothelium where it is completely broken down chemically and eliminated [Frazer et al., Clin. Exp. Phar . Phys. f Vol. 11, pages 17-25, 1984].
  • Balazs and Denlinger [CIBA Foundation Symp. #143, pp.
  • HA gel viscosity increases linearly with concentration in solution. Since (1) the gel's seepage (preferential extrusion) through the paste decreases with increasing viscosity, (2) gel seepage must be avoided to ensure good quality injections, and (3) a 2% HA solution is still sufficiently pliable to allow easy manipulation, but minimizes seepage, a 2% HA solution is preferably used in the paste.
  • a given quantity of glass particulates of 45-120 mesh were weighed and a 1% HA solution was added as required to produce ratios from 0.33 glass/HA to 1.6 glass/HA.
  • the powder and polymer were mixed with a spatula using a stirring and spreading motion until homogeneity was achieved (approximately one minute) .
  • the paste was loaded into the top of a large syringe and then injected into a smaller syringe with has a 16 or 20 gauge needle or no needle. It was discovered that this method of loading eliminates air bubbles in the paste.
  • the paste was injected through the needle using moderate speed and pressure, and the relative smoothness of the injected volume was noted by manual manipulation. Segregation of the polymer, which must be avoided, eliminated glass particles from the injected material which could be detected by feeling it, although microscopy was also used to verify the findings.
  • the relative roundness of the glass particles also affects the rheology of the paste and the optimal ratio of glass to HA.
  • the optimal ratio is 0.4, as determined above. With completely round particles, the ratio can be increased slightly when all other parameters are unchanged. The final optimal ratio, however, will be slightly less than 0.4.
  • Rounding of the crushed glass sufficient to improve the rheology can be accomplished by milling dry without a milling medium for 48 hours and sieving off the finer particles.
  • the configuration of the syringe used for the delivery of the injectable paste is also an important variable for optimizing the method of the invention.
  • a design which minimizes the force needed for paste injection and thus maximizes the amount of glass in the paste and minimizes the seepage of HA during extrusion at clinical injection rates is given in Fig. 2.
  • the critical design features are barrel and die L/D ratios, barrel/die diameter ratios and the die taper angle.
  • a syringe/needle assembly consists of barrel 12, plunger 14 and syringe tip 16.
  • Preferred dimensions of the assembly for injecting optimum pastes according to the invention are as follows:
  • the thickness represented by arrows (a) of the plunger cap 18 and grip flange 20 is 0.1 cm.
  • the diameter of the plunger cap [arrow (b) ] is 1.414 cm.
  • the diameter of the grip flange [arrow (c) ] is 1.714 cm.
  • the length of the barrel [arrow (d) ] is 11.5 cm.
  • the distance [arrow (e) ] between the plunger cap 18 and grip flange when fully depressed is 0.5 cm.
  • the distance between the plunger cap 18 and the end of the barrel [arrow (f) ] when fully depressed is 12.0 cm.
  • the diameter [arrow (g) ] of the plunger is 0.614 cm and the inner diameter [arrow (h) ] of the barrel is 0.714 cm.
  • the length of the taper of the proximal end of the barrel to the beginning of the syringe tip 16 [arrows (i)] is 0.166 cm.
  • the angle ( ⁇ ) between the tape wall at the end of barrel 12 and the longitudinal axis of the barrel 12 is 65°.
  • the taper of the syringe tip 16 from the end of the barrel 12 is a standard Luer taper.
  • the outer diameter of the proximal end of the syringe tip 16 is 0.155 cm.
  • the length of the tapered syringe tip 16 [arrow (j)] is 0.170 cm.
  • the ideal syringe volume is a compromise between ease of use and sufficient paste volume delivery. Since a total of 10- 12 ml of the paste needs to be injected in at least three sites in clinical practice to treat urinary incontinence, a 3-4 ml syringe is desirable. Also, experiments show that the least force is needed to inject pastes when the syringe volume is about 4 ml (Fig. 3) . This is totally unexpected in view of the theoretical predictions for injectable mixtures.
  • the particle sizes ranged from 100-355 ⁇ m and were suspended in medical grade HA acid, so as to be injectable through a #16 needle.
  • An injection of 0.1 ml was made into the dome of the bladder in rabbits and subcutaneous injections of both suspensions and of the HA acid alone were made (six subcutaneous injections in each animal) .
  • Two rabbits were killed after each of 2, 4, 6, 8, 10 and 12 weeks. All experimental sites were examined microscopically, as were major internal organs. Samples of liver, kidney, lungs and lymph nodes were digested and analyzed by AAS for silicon from migrating particles.
  • Particulate material was present in 67% of injection sites in the bladder overall. No difference in tissue response was seen between glass compositions. Soft tissue bonding to the particles' surface was seen at all time periods. There was persistent cellularity within the particulate mass at all time periods, although there was no inflammation in adjacent tissues and the urothelium was invariably normal.
  • Subcutaneous sites which contained HA were completely normal at all time periods. The material could not be detected by normal histological techniques. There was no difference between glass compositions at any time. Many of the injections were in the subdermal muscle planes rather than subcutaneous tissues. Tissue response showed bonding of soft tissues at all time intervals, but with persistent cellularity throughout the experimental period. Particles toward the periphery of the mass had thin collagenous tissue around them and no macrophages at the interface and those in the center had macrophages, giant cells and some focal inflammation between them. There was no inflammatory infiltrate in surrounding tissues. In some cases, the central part of the lesion was infarcted, although the peripheral particles were bonded in place.
  • HA injected sites were completely normal at all time periods.
  • the tissue response to the glass materials was evaluated using the following criteria:
  • the tissue response was variable. Soft tissue bonding was seen from four weeks, but phagocytes were present at all time intervals, although reducing in numbers throughout the experimental period.
  • the outside of the mass was generally relatively acellular stable connective tissue, the inside was often more cellular and the fibers more fragile. Some masses had foci of degenerative change centrally. These effects are due to mechanical abrasion of the ingrowing collagen fibers and the new capillaries by the glass particles. There was no inflammation or infiltration of adjacent tissues. No difference was seen between 45S5 and 43S5 4F bio-active glass sites.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Oral & Maxillofacial Surgery (AREA)
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Abstract

Composition de verre bioactive injectable particulaire d'acide hyaluronique utile dans la réparation, la reconstitution, le remplacement, l'augmentation ou la reconfiguration d'os dur ou de structure anatomique à tissu tendre, la composition du verre se trouvant à l'intérieur de la région E du diagramme de délimitation de la composition de la figure 4.
PCT/US1991/003596 1990-05-22 1991-05-22 Compositions de verre bioactives injectables et procede de reconstitution de tissus WO1991017777A2 (fr)

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US52663890A 1990-05-22 1990-05-22
US526,638 1990-05-22

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WO1991017777A2 true WO1991017777A2 (fr) 1991-11-28
WO1991017777A3 WO1991017777A3 (fr) 1992-01-09

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WO1993020858A1 (fr) * 1992-04-17 1993-10-28 Fidia S.P.A Biomateriaux utilises pour remplacer des os
WO1996010985A1 (fr) * 1994-10-06 1996-04-18 Bioxid Oy Nouvelles utilisations de verres a la silice bioactive et nouvelles preparations les contenant
US5591724A (en) * 1995-02-14 1997-01-07 Bioniche Inc. Method for treating the urinary bladder and associated structures using hyaluronic acid
US5591453A (en) * 1994-07-27 1997-01-07 The Trustees Of The University Of Pennsylvania Incorporation of biologically active molecules into bioactive glasses
WO1998044965A1 (fr) * 1997-04-05 1998-10-15 Giltech Limited Composition pour implants a base de particules de verre
EP0910350A1 (fr) * 1996-05-09 1999-04-28 The Trustees Of The University Of Pennsylvania Stabilisation de verre a base de silice derive d'un sol-gel
US5977204A (en) * 1997-04-11 1999-11-02 Osteobiologics, Inc. Biodegradable implant material comprising bioactive ceramic
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US6479565B1 (en) 1999-08-16 2002-11-12 Harold R. Stanley Bioactive ceramic cement
FR2850282A1 (fr) * 2003-01-27 2004-07-30 Jerome Asius Implant injectable a base de ceramique pour le comblement de rides, depressions cutanees et cicatrices, et sa preparation
EP1454640A2 (fr) * 1999-10-15 2004-09-08 Genetics Institute, LLC Formulations d'acide hyaluronique pour la libération de protéines osteogéniques
US7060287B1 (en) 1992-02-11 2006-06-13 Bioform Inc. Tissue augmentation material and method
WO2008032054A2 (fr) * 2006-09-15 2008-03-20 Novathera Limited Matériau composite
US7524335B2 (en) 1997-05-30 2009-04-28 Smith & Nephew, Inc. Fiber-reinforced, porous, biodegradable implant device
EP2063859A1 (fr) * 2006-09-13 2009-06-03 Enhance Skin Products, Inc. Composition cosmétique pour le traitement de la peau et procédés correspondants
US7622139B2 (en) 2001-06-08 2009-11-24 Wyeth Calcium phosphate delivery vehicles for osteoinductive proteins
WO2009144453A1 (fr) * 2008-05-27 2009-12-03 Imperial Innovations Limited Verres de stabilisation du facteur inductible par l’hypoxie (hif)
US7842300B2 (en) 2002-07-31 2010-11-30 Dentsply International, Inc. Bone repair putty
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US7968110B2 (en) 1992-02-11 2011-06-28 Merz Aesthetics, Inc. Tissue augmentation material and method
US8093166B2 (en) 2006-09-20 2012-01-10 Inion Oy Bioactive glass compositions
US8876532B2 (en) 2002-07-31 2014-11-04 Dentsply International Inc. Bone repair putty
EP2823829A1 (fr) 2007-04-23 2015-01-14 Baxter International Inc. Compositions à base de fibrine contenant des composés de strontium pour stimuler l'ossification
US9198842B2 (en) 2009-06-30 2015-12-01 Repregen Limited Multicomponent glasses for use in personal care products
US9421302B2 (en) 2006-05-26 2016-08-23 Baxter International Inc. Injectable fibrin composition for bone augmentation
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US11464740B2 (en) 2019-04-29 2022-10-11 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Method and devices for delivering therapeutics by oral, respiratory, mucosal, transdermal routes

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