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WO2008013962A2 - Procédé et mélange pour la réticulation photochimique in vivo du collagène - Google Patents

Procédé et mélange pour la réticulation photochimique in vivo du collagène Download PDF

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Publication number
WO2008013962A2
WO2008013962A2 PCT/US2007/016952 US2007016952W WO2008013962A2 WO 2008013962 A2 WO2008013962 A2 WO 2008013962A2 US 2007016952 W US2007016952 W US 2007016952W WO 2008013962 A2 WO2008013962 A2 WO 2008013962A2
Authority
WO
WIPO (PCT)
Prior art keywords
collagen
photosensitizer
linking
vivo
cross
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2007/016952
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English (en)
Other versions
WO2008013962A3 (fr
WO2008013962A9 (fr
Inventor
Susanna Grafe
Wolfgang Neuberger
Danilo Castro
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ceramoptec Industries Inc
Original Assignee
Ceramoptec Industries 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
Priority claimed from US11/880,973 external-priority patent/US20090028926A1/en
Application filed by Ceramoptec Industries Inc filed Critical Ceramoptec Industries Inc
Priority to US12/227,079 priority Critical patent/US8263557B2/en
Priority to EP07810866A priority patent/EP2068622A4/fr
Publication of WO2008013962A2 publication Critical patent/WO2008013962A2/fr
Publication of WO2008013962A9 publication Critical patent/WO2008013962A9/fr
Publication of WO2008013962A3 publication Critical patent/WO2008013962A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • 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
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]

Definitions

  • Present invention relates to structural proteins like collagen repairs in general, while, more specifically it relates to a method of photochemical cross linking of collagen fibrils using photoactive agent, whereby it could be used in different types of tissue repair and regeneration in human and animals.
  • collagen is the main substance of connective tissue and is present in humans. In mammals collagen is the most abundant protein. Collagen gives many different organs and tissues support and elastic properties. It has been found in many different tissues and organs like bones, tendons, (hyaline) cartilage, blood vessels, teeth, cornea, skin, etc. It prevents organs/tissues to tear or loose their functional shape when they are exposed to sudden and wild movements.
  • Collagens are fibrous protein composed on amino acids. The most abundant amino acids are glycine, proline and hydroxyproline.
  • General collagen structure consists of three polypeptides, each of which is a left-handed helix, intertwined into a right-handed triple helix. Human body is mainly composed of collagen type I. II. Ill, however many other types are also present.
  • Collagen is a natural biomaterial commonly used in tissue engineering and repair; it has negligible immune rejection and excellent biocompatibility. But unprocessed collagen is mechanically weak and vulnerable to chemical and enzymatic attacks that limits its use.
  • Collagen can be cross-linked to increase its molecular stability and mechanical properties.
  • the most basic mode of action is the covalent intermolecular cross-link formation between collagen fibrils.
  • Cross-linking improves strengths, resorption rate and biocompatibility of the scaffold.
  • the collagen can be strengthen and stabilized, either by chemical or physical methods of cross-linking.
  • some chemical cross-linking agents include: glutaraldehyde, formaldehyde, l -ethyl-3(3-dimethylaminopropyl)- carbodimide (EDC) etc are used for cross-linking to improve the Physico-chemical properties of collagen; however, this method is limited because of induction of cytotoxicity and calcification and stiffness in host tissue due to incomplete removal of the toxic residues, aldehydes, and other metabolites.
  • Physical methods of cross-linking can be achieved by heat, dehydrothermal treatment (DHT), and UV- and ⁇ -irradiation.
  • Photochemical method provides an alternative method for cross-linking collagen in the presence of light and photosensitizing agents.
  • US patent 6,783,539 by Timberlake et al. discloses uses of phototriggerable tethered diazopyruvate composition and method for crossing linking of proteins using the same.
  • a wavelength range of 330-400nm is used for activation of photoactive compound and cross-linking of the protein. The wavelength range used here minimal penetration and is useful only for certain medical application.
  • Cross-linking is done prior to application in vivo.
  • a better method of collagen cross linking needs to be developed which would in turn improve the physio-chemical properties of collagen such as water-binding capacity, mechanical properties and thermostability thus enhancing better tissue healing without scaring or damaging the collagen.
  • the present invention aims to provide this.
  • present invention provides a method and compositions for photochemical cross linking of collagen by photoactive agent in-vivo.
  • the method includes a non-toxic photoactive formulation of the composition with collagen, which is administered to treatment area locally followed by irradiation with suitable wavelength.
  • liposomal formulated mTHPC is added to the collagen and is irradiated with a 652 nm laser, resulting in producing efficient collagen scaffolds with strengthened and stabilized micro structure, thus improving the physiochemical properties of the collagen scaffold. It improves the thermostability, mechanical property and swelling ratio of newly formed scaffold.
  • Photochemical cross-linking of collagen in vivo also shows an antimicrobial effect. When irradiated with a suitable wavelength, it disinfects the treatment site and curbs microbial growth.
  • Fig. 1 - depicts the non-irradiated collagen picture with mTHPC.
  • Fig. 2 - show a picture of collagen with mTHPC after irradiation.
  • Fig. 3 - shows biopsy results 14 days after treatment in mice.
  • Fig. 4 - depicts the antimicrobial effect of collagen /mTHPC mixture
  • Fig 5a - shows pictures before using the collagen and mTHPC filler product on lips.
  • Fig 5b - show the lip picture after 9 month of using collagen and mTHPC filler product.
  • Fig. 6 before and after pictures of wound repair with present invention
  • Collagen is a natural biomaterial used for tissue reconstruction in third degree burns, wounds and for cosmetic application.
  • Collagen as currently available has several drawbacks like being mechanically weak, low stability, swelling rapidly in water and being susceptible to chemical and enzymatic attack when implanted.
  • Physiochemical properties of collagen fibers are somewhat improved by physical or chemical method of cross-linking.
  • Collagens cross-linked by chemical methods however, have a risk of potential toxicity of residual molecules or compounds after implantation. While in the physical method, there is risk of denaturation of protein.
  • Photochemical cross-linking provides an alternative method to chemical and physical method of cross-linking collagen. Photochemical reactions of collagen in presence of light and photosensitizing agent causing cross-linking of collagen gives better physiochemical properties and also a non-cytotoxic collagen scaffold.
  • Photochemical cross-linked collagen has fine microstructure with interconnected nano-sized fibers forming micron-sized pores.
  • the pore size is important in scaffold as they will determine cell adhesion and migration of the scaffold and as a result the success of healing.
  • Photochemical cross-linking is able to stabilize the bonding forces between molecules and fibers so that the strengthened microstructure can survive a freeze-drying process. It also stabilizes the collagen scaffold thermally.
  • a method for photochemical cross-linking of collagen using photoactive compound includes a non-toxic photoactive formulation for hydrophobic photosensitizer/ precursor of photosensitizer with collagen, wherein preferably the hydrophobic photosensitizer is formulated into liposomes.
  • the photoactive formulation is administered to the tissue either as injectable solution, sponge or wound dressing; this is followed by a short drug-light- interval (DLI) and, then, by irradiation with wavelength which activates selected photosensitizer.
  • the photochemical reaction and the release of singlet oxygen causes a) disinfection of the treated area, and b) photochemical cross-linking of collagen by
  • collagen is used in combination with liposomal formulated temoporfm (chemical name: m-tetrahydroxyphenylchlorin, (mTHPC)) after a short DLI it is irradiated with a deeper penetrating 652 nm wavelength to produce efficient collagen scaffolds with strengthened and stabilized microstructures. It improves the physicochemical properties of the scaffolds, including the thermostability, mechanical properties and swelling ratio.
  • the method used here in general is: 1.
  • Collagen equine or bovine collagen fibrils, 0.01 up to 5 %, pH of the solution 6.0 to
  • mTHPC photoactive dye, temoporfm, 5,10,15,20-tetra [m-hydroxyphenyl]chlorin
  • Liposomal Formulation of mTHPC 1.5 mg/ml mTHPC, 6.0 mg/ml of dipalmitoylphosphatidylcholine (DPPC), 0.70 mg/ml of dipalmitoylphosphatidylglycerol (DPPG), 17.0 mg/ml of glucose and
  • the final concentration of mTHPC will be approx. 0.05 mg/ml.
  • the formulation is irradiated with 652 nm.
  • a laser PDT laser Ceralas 652 nm, Biolitec AG
  • Lamp with appropriate wavelength could be used.
  • Energy density of the light is about 10 to 20 J/cm 2 for in vivo cases.
  • For production of collagen sponges ex vivo a higher density is commonly used, e.g. 100 J/cm 2 .
  • a 10 to 100 J/cm 2 energy density can be used in the present invention.
  • the photochemical product, obtained of the above reaction, is better stabilized in structure with increased hydrothermal properties and resistance to enzymatic degradation.
  • Another embodiment of the present invention is use of fluorescence dye (mTHPC) in this formulation, and then the collagen fibril formation in the scaffold after irradiation with laser light can be controlled by break down of fluorescence of the dye.
  • the light activated photosensitizing dye (mTHPC) is producing singlet oxygen to oxidize surrounding molecules (collagen cross-linking) and will bleach during this process.
  • Example 1 The present invention is further illustrated by the following examples, but is not limited thereby.
  • Example 1 The present invention is further illustrated by the following examples, but is not limited thereby.
  • Example 1 Example 1:
  • the liposomal formulation of mTHPC was added to this.
  • the final concentration of mTHPC in the formulation was 0.03 mg/ml.
  • the formulation is irradiated with 652 nm laser (Ceralas, Biolitec AG) and 100 J/cm 2 .
  • the photochemical product have been investigates macroscopically and microscopically. Macroscopically the viscosity of the irradiated solution was higher than of the non-irradiated solution. Larger particles could be visible to the naked eye.
  • Microscopically collagen fibrils in the irradiated solution are forming larger and more compact aggregates refer figure 2 than in the non-irradiated solution refer figure 1.
  • BaIb c mice were used for the study. Selected mice were narcotized and a small cut was inflicted in the neck region. Three treatment groups are set up: in the first treatment group a 5x5 mm piece of collagen saturated with liposomal formulation of mTHPC is implanted under the skin. After 30 min of incubation the area is irradiated with light at 652nm at 10 J/cm 2 after which the region is covered with catgut and Hansaplast plaster spray.
  • Third group is the control where in the mice wound is treated using collagen and laser irradiation with no liposomal formulation of mTHPC.
  • Collagen products used in this treatment includes Gentacoll, Kollagen Resorb and collagen fibrils.
  • 2 mice each is treated, for, each of these collagen products.
  • mice were kept under observation to record the progress in wound healing.
  • the progress in the wound healing process was recorded after 24 hours from treatment. It was noticed that all mice in treatment group 2 showed very good response with slight inflammation and wound was healed well; with all animals being vital in the group, while mice in treatment group 1 had shown strong redness and inflammation with hair loss in the treated area but the wound healing process was good by 12 days with hair growing back in the areas if treatment.
  • Control group 3 showed very strong inflammatory action with redness and strong swelling in the initial period of treatment.
  • AU mice treated with collagen fibrils showed best biocompatibility compared to other collagen products used.
  • a mixture of a commercial collagen formulation (Zyplast) and a liposomal formulation of mTHPC was used as a dermal filler of lips.
  • the mTHPC concentration was 0.05 mg/ml and the Hp was irradiated by laser light at 652 nm. Due to the cross- linking of the collagen by mTHPC we could observe a longer lasting filling effect of the upper Hp.
  • Usually commercial collagen products will be resorbed within 4 to 6 month after injection.
  • Figure 5a shows the picture of before using filler and figure 5b shows the effect of the filler after 9 months.
  • Figure 6 shows the open wound before and after being treated with photochemical cross-linked collagen and irradiation.
  • the open wound of the figure 6 is cleaned and disinfection before implanting the collagen matrix and liposome entrapped mTHPC mixture. After incubating for 1 hour the wound is irradiated with laser at 652nm, and 20J/cm 2 .
  • the laser irradiation helps in cross-linking the collagen fibrils and also disinfects the treatment area of microbial growth.
  • the figure 6 shows the result of treatment after 3 days.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Toxicology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Transplantation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé et une composition pour la réticulation photochimique du collagène par un agent photoactif in vivo. Le procédé comprend l'administration locale à une zone de traitement d'une formulation photoactive non toxique de la composition avec le collagène, suivie par une irradiation avec une longueur d'onde appropriée. Dans l'un des modes de réalisation, la mTHPC formulée en liposomes est ajoutée au collagène et est irradiée par un laser de 652 nm, conduisant à la production d'échafaudages efficaces de collagène ayant une microstructure renforcée et stabilisée, permettant ainsi d'améliorer les propriétés physico-chimiques de l'échafaudage de collagène. Elle améliore la thermostabilité, la propriété mécanique et le rapport de gonflement de l'échafaudage nouvellement formé. Un collagène photochimiquement réticulé présente un effet antimicrobien, lorsqu'il est irradié par une longueur d'onde appropriée, il désinfecte le site de traitement et réfrène la croissance microbienne.
PCT/US2007/016952 2006-07-28 2007-07-27 Procédé et mélange pour la réticulation photochimique in vivo du collagène Ceased WO2008013962A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/227,079 US8263557B2 (en) 2006-07-28 2007-07-27 Method and mixture for in vivo photochemical cross-linking of collagen
EP07810866A EP2068622A4 (fr) 2006-07-28 2007-07-27 Procédé et mélange pour la réticulation photochimique in vivo du collagène

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US83405906P 2006-07-28 2006-07-28
US60/834,059 2006-07-28
US11/880,973 US20090028926A1 (en) 2007-07-25 2007-07-25 Method and mixture for in vivo photochemical cross-linking of collagen
US11/880,973 2007-07-25

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WO2008013962A2 true WO2008013962A2 (fr) 2008-01-31
WO2008013962A9 WO2008013962A9 (fr) 2008-03-27
WO2008013962A3 WO2008013962A3 (fr) 2008-12-18

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010051636A1 (fr) 2008-11-07 2010-05-14 Klox Technologies Inc . Combinaison d’un oxydant et d’un photoactivateur destinée à la cicatrisation
US8685466B2 (en) 2009-07-17 2014-04-01 Klox Technologies Inc. Combination of an oxidant, a photosensitizer and a wound healing agent for oral disinfection and treatment of oral disease
US8986719B2 (en) 2005-11-09 2015-03-24 Klox Technologies Inc. Teeth whitening compositions and methods
WO2015084972A1 (fr) 2013-12-03 2015-06-11 Cornell University Procédé pour réparer un espace annulaire, et composition de gel de collagène
US9345648B2 (en) 2006-11-09 2016-05-24 Klox Technologies Inc. Photoactivatable oxygen-evolving compositions and methods for teeth whitening
US9655829B2 (en) 2012-09-14 2017-05-23 Valeant Pharmaceuticals International, Inc. Compositions and methods for teeth whitening
US10130706B2 (en) 2013-03-14 2018-11-20 Klox Technologies Inc. Biophotonic materials and uses thereof
US10207029B2 (en) 2014-04-01 2019-02-19 Klox Technologies Inc. Tissue filler compositions and methods of use
US10213373B2 (en) 2012-04-20 2019-02-26 Klox Technologies, Inc. Chromophore combinations for biophotonic uses
US10881736B2 (en) 2013-07-03 2021-01-05 Klox Technologies Inc. Biophotonic compositions comprising a chromophore and a gelling agent for treating wounds
US11116841B2 (en) 2012-04-20 2021-09-14 Klox Technologies Inc. Biophotonic compositions, kits and methods
US11421349B2 (en) 2014-10-31 2022-08-23 Klox Technologies Inc. Photoactivatable fibers and fabric media
CN116099049A (zh) * 2023-01-20 2023-05-12 广州希倍医疗科技有限公司 一种改性胶原蛋白支架的制备方法及其产品和应用

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See also references of EP2068622A4

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8986719B2 (en) 2005-11-09 2015-03-24 Klox Technologies Inc. Teeth whitening compositions and methods
US9345648B2 (en) 2006-11-09 2016-05-24 Klox Technologies Inc. Photoactivatable oxygen-evolving compositions and methods for teeth whitening
US8986745B2 (en) 2008-11-07 2015-03-24 Klox Technologies Inc. Oxidatitive photoactivated skin rejeuvenation composition comprising hyaluronic acid, glucosamine, or allantoin
WO2010051636A1 (fr) 2008-11-07 2010-05-14 Klox Technologies Inc . Combinaison d’un oxydant et d’un photoactivateur destinée à la cicatrisation
US11691025B2 (en) 2008-11-07 2023-07-04 Klox Technologies Inc. Methods and compositions for reversing or mitigating skin aging
US8911791B2 (en) 2008-11-07 2014-12-16 Klox Technologies Inc. Method for acne treatment using an oxidative-photoactivated composition
US8974833B2 (en) 2008-11-07 2015-03-10 Klox Technologies Inc. Combination of an oxidant and a photoactivator for the healing of wounds
US8637086B2 (en) 2008-11-07 2014-01-28 Klox Technologies Inc. Method for acne treatment using an oxidative-photoactivated composition
US10149985B2 (en) 2008-11-07 2018-12-11 Klox Technologies Inc. Methods and compositions for treating rosacea
US8658219B2 (en) 2008-11-07 2014-02-25 Klox Technologies Inc. Oxidatitive photoactivated skin rejeuvenation composition comprising hyaluronic acid, glucosamine, or allantoin
US11020609B2 (en) 2008-11-07 2021-06-01 Klox Technologies Inc. Methods and compositions for treatment of pigmented lesions
US8632822B2 (en) 2008-11-07 2014-01-21 Klox Technologies Inc. Combination of an oxidant and a photoactivator for the healing of wounds
US9375446B2 (en) 2008-11-07 2016-06-28 Klox Technologies Inc. Oxidatitive photoactivated skin rejeuvenation composition comprising hyaluronic acid, glucosamine, or allantoin
US9597349B2 (en) 2008-11-07 2017-03-21 Klox Technologies Inc. Combination of an oxidant and a photoactivator for the healing of wounds
US10758744B2 (en) 2008-11-07 2020-09-01 Klox Technologies Inc. Combination of an oxidant and a photoactivator for the wounds
US10485986B2 (en) 2008-11-07 2019-11-26 Klox Technologies Inc. Methods and compositions for treatment of pigmented lesions
EP3205355A1 (fr) 2008-11-07 2017-08-16 KLOX Technologies, Inc. Combinaison d'un oxydant et d'un photoactivateur
US10384072B2 (en) 2008-11-07 2019-08-20 Klox Technologies Inc. Combination of an oxidant and a photoactivator for the healing of wounds
US8986746B2 (en) 2009-07-17 2015-03-24 Klox Technologies Inc. Combination of an oxidant, a photosensitizer and a wound healing agent for oral disinfection and treatment of oral disease
US8685466B2 (en) 2009-07-17 2014-04-01 Klox Technologies Inc. Combination of an oxidant, a photosensitizer and a wound healing agent for oral disinfection and treatment of oral disease
US10322179B2 (en) 2009-07-17 2019-06-18 Klox Technologies Inc. Combination of an oxidant, a photosensitizer and a wound healing agent for oral disinfection and treatment of oral disease
US11141482B2 (en) 2009-07-17 2021-10-12 Klox Technologies Inc. Combination of an oxidant, a photosensitizer and a wound healing agent for oral disinfection and treatment of oral disease
US10471147B2 (en) 2009-07-17 2019-11-12 Klox Technologies Inc. Combination of an oxidant, a photosensitizer and a wound healing agent for oral disinfection and treatment of oral disease
US9603929B2 (en) 2009-07-17 2017-03-28 Klox Technologies Inc. Combination of an oxidant, a photosensitizer and a wound healing agent for oral disinfecton and treatment of oral disease
US10213373B2 (en) 2012-04-20 2019-02-26 Klox Technologies, Inc. Chromophore combinations for biophotonic uses
US10376455B2 (en) 2012-04-20 2019-08-13 Klox Technologies Inc. Biophotonic compositions and methods for providing biophotonic treatment
US11331257B2 (en) 2012-04-20 2022-05-17 Klox Technologies Inc. Biophotonic compositions and methods for providing biophotonic treatment
US11723854B2 (en) 2012-04-20 2023-08-15 Fle International S.R.L. Biophotonic compositions and methods for providing biophotonic treatment
US11116841B2 (en) 2012-04-20 2021-09-14 Klox Technologies Inc. Biophotonic compositions, kits and methods
US9655829B2 (en) 2012-09-14 2017-05-23 Valeant Pharmaceuticals International, Inc. Compositions and methods for teeth whitening
US10130706B2 (en) 2013-03-14 2018-11-20 Klox Technologies Inc. Biophotonic materials and uses thereof
US11324823B2 (en) 2013-03-14 2022-05-10 Klox Technologies Inc. Biophotonic materials and uses thereof
US10881736B2 (en) 2013-07-03 2021-01-05 Klox Technologies Inc. Biophotonic compositions comprising a chromophore and a gelling agent for treating wounds
WO2015084972A1 (fr) 2013-12-03 2015-06-11 Cornell University Procédé pour réparer un espace annulaire, et composition de gel de collagène
EP3076902B1 (fr) * 2013-12-03 2025-02-05 Cornell University Procédé pour réparer un espace annulaire, et composition de gel de collagène
US10207029B2 (en) 2014-04-01 2019-02-19 Klox Technologies Inc. Tissue filler compositions and methods of use
US10772990B2 (en) 2014-04-01 2020-09-15 Klox Technologies Inc. Tissue filler compositions and methods of use
US11421349B2 (en) 2014-10-31 2022-08-23 Klox Technologies Inc. Photoactivatable fibers and fabric media
CN116099049A (zh) * 2023-01-20 2023-05-12 广州希倍医疗科技有限公司 一种改性胶原蛋白支架的制备方法及其产品和应用

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Publication number Publication date
WO2008013962A3 (fr) 2008-12-18
WO2008013962A9 (fr) 2008-03-27
EP2068622A4 (fr) 2012-10-10
EP2068622A2 (fr) 2009-06-17

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