WO2011061561A2 - Procédé destiné à obtenir des matrices moléculaires régénératrices et matrices moléculaires régénératrices ainsi obtenues - Google Patents
Procédé destiné à obtenir des matrices moléculaires régénératrices et matrices moléculaires régénératrices ainsi obtenues Download PDFInfo
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- WO2011061561A2 WO2011061561A2 PCT/IB2009/055180 IB2009055180W WO2011061561A2 WO 2011061561 A2 WO2011061561 A2 WO 2011061561A2 IB 2009055180 W IB2009055180 W IB 2009055180W WO 2011061561 A2 WO2011061561 A2 WO 2011061561A2
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
Definitions
- the present application relates to a method for obtaining regenerative molecular matrices that induce, by cellular signaling, the selective differentiation of mesenchymal stem cells present in all connective tissues. Additionally, the matrix obtained by said method is claimed, which has regenerative properties of hard and soft connective tissues with uses for both humans and animals.
- the disclosed matrix is relevant for multiple applications, among others, for the regeneration of soft tissues, such as mucosa and skin; hard tissue regeneration, including bone and cartilage; epithelial regeneration and keratinization; tissue adhesion, scarring, preservation and implantation of autologous or cultured cells, reduction or elimination of post-surgical paresthesias, local hemostasis, local release and transfer of molecules and medications, bioabsorbable matrices with barrier effect (guided bone regeneration or guided periodontal regeneration), neovascularization and tissue revascularization, optimization of reimplantation of structures or tissues lost due to trauma, prosthetic osseointegration, etc.
- soft tissues such as mucosa and skin
- hard tissue regeneration including bone and cartilage
- epithelial regeneration and keratinization tissue adhesion, scarring, preservation and implantation of autologous or cultured cells, reduction or elimination of post-surgical paresthesias, local hemostasis, local release and transfer of molecules and medications
- bioabsorbable matrices with barrier effect guide
- the matrix of the invention is useful in craniofacial surgery, general surgery, maxillofacial surgery, plastic, reconstructive, cosmetic, skin rejuvenation, dermatology, diabetology, gastroenterology, cardiovascular and thoracic medicine, sports medicine, vascular medicine , veterinary medicine, neurosurgery, dentistry, ophthalmology, orthopedics and traumatology, otolaryngology, burns and urology, among others.
- the matrix can be used in current alternative therapies such as prolotherapy for cases of: myofacial pain syndrome, Achilles tendinosis, patellar tendinosis or quadricipital tendinosis, rotator cuff tendinosis or "bursitis” or “tennis elbow” or “tennis elbow” golfer ", chronic sprains of the ankle and knee, partial ruptures of ligaments, pubalgia, osteoarthritis, plantar fasciitis, low back pain, cervicalgia and dorsalgia of myofascial or musculo-tendino-ligament origin and sacroiliac dysfunction, among others.
- therapies such as prolotherapy for cases of: myofacial pain syndrome, Achilles tendinosis, patellar tendinosis or quadricipital tendinosis, rotator cuff tendinosis or "bursitis” or “tennis elbow” or “tennis elbow” golfer ", chronic sprain
- platelet-rich gels or platelet-rich plasmas have been produced by precipitation procedures in a blood package collected at the bottom of a specific vessel, under the protocol of each of the companies promoting these processes.
- AGF Autologous Growth Factors or growth factors of autologous origin
- AGF systems also began to be developed by different companies in the world, finding procedural and final characterization differences between them, such differences that included the addition of thrombin of bovine origin and the indispensable use of packages of disposable attachments necessary to perform the procedure.
- these methodologies involved different equipment, times, phases and centrifugation speeds, consistent with the manufacturer's own standardization but different from each other. Its characteristics of composition and platelet quality also vary among themselves.
- fibrin glue conceived as substances that applied to a tissue improves or allows its adhesion to another tissue. This type of glue was also used with teeth lost in accidents (dento-alveolar trauma) to reimplant them later. Usually a solution was used Hanks saline or medium to preserve them, but the subsequent risk of necrosis is very high.
- PRP Platelet Rich Plasma
- PRGF Rowth Factor Rich Plasma
- PRFF Fibrin Rich Plasma
- the aforementioned plasmas comprise cellular contents such as platelets in variable numbers according to the equipment and procedure time used, with averages of final platelet concentration of 700 310 3 / ⁇ to 1800x10 3 / ⁇ , this concentration does not guarantee the biological viability of the growth factors contributed.
- these plasmas there are quantities of red blood cells in varying final concentrations depending on the equipment and the duration of the procedure used and in average ranges of 1.5 to 3.7 x 10 6 / ⁇ _.
- the leukocyte concentrations reported for this type of plasmas range between 0.5 and 10.9 x 10 3 / ⁇ , depending on the device and the procedure time used, confirming the variability described.
- the centrifuges used to obtain and handle these concentrates are characterized by having conical rotors of varying diameter and angle, in which the centrifugal force ranges from 800 to 3500 rpm and the centrifugation times they fluctuate between 3 to 30 minutes, depending on the research group that generates the publication.
- the volume of anticoagulated sample used as the basis for the preparation of the concentrates has varied from 450 to 500 ml_ of anticoagulated blood with ACD (41 mM Citric Acid / Citrate Citrate). 100 mM Sodium / 136 mM Glucose), for the initial processes of PRP, and some other methods currently available start from a sample quantity that ranges from 50 to 150 ml_ of anticoagulated blood with ACD or CTS (Trisodium Citrate 0.109 mol / L).
- the applicant developed a method for obtaining growth factors, fibrin and Autologous thrombin applying a standardized methodology that included a single phase of centrifugation and guaranteed total absence of erythrocyte and leukocyte residues, thus eliminating undesirable reactions in the recipient tissue and preserving platelet functionality.
- FIGURE 1 A to D. Soft tissue. Comparative regeneration of the action of the material reported in CO 05-034788 and regeneration with the biomaterial of the present invention.
- FIGURE 2A to H Hard tissue. Comparative regeneration of the action of the material existing in the state of the art and regeneration with the biomaterial of the present invention as a function of time.
- FIGURE 3A to 3D Comparative regeneration of the action of the material existing in the state of the art and the biomaterial of the present invention in the management of gingival retractions due to periodontal disease.
- FIGURE 5A to D Adherence and comparative regeneration of the action between the material existing in the state of the art and the biomaterial of the present invention.
- FIGURE 6A to E Location and healing of ocular fistulas with the biomaterial of the present invention.
- the present application refers to a standardized method for obtaining regenerative and autologous molecular matrices based on growth factors, fibrin, fibronectin and thrombin to be applied to the same patient in the form of a three-dimensional matrix that allows to achieve a tissue regeneration at the molecular level patients with alterations or deficiencies of hard and soft tissues.
- This procedure generates a biomaterial with total platelet viability, free of erythrocytes, leukocytes, pro-inflammatory factors (interleukins) and cellular waste, and with a three-dimensional scaffolding behavior that optimizes the times and quality of the regenerative process achieved.
- the biomaterial obtained by said method and the uses of this material in different applications of the medical and veterinary field is part of the invention. Specifically, the applicant has found that unexpectedly replacing the centrifugation stage with a gravitational separation in a single phase followed by differential sedimentation allows him to obtain a three-dimensional matrix that optimizes the regenerative process in terms of quality and time.
- the process claimed here is characterized in that it comprises the following steps: a. Obtain blood from the patient, by standardized phlebotomy without the use of a tourniquet and use of a sterile vacuum system,
- the amount of blood taken from the patient in step a) ranges from 5ml to 30ml and according to the state of hemoconcentration (Hematocrit) is collected in 4 to 6 sterile tubes with anticoagulant, including CM1, Trisodium Citrate Buffered 0.109 M, pH 7.4, trisodium citrate 3.8, ADP citrate dextrose.
- anticoagulant including CM1, Trisodium Citrate Buffered 0.109 M, pH 7.4, trisodium citrate 3.8, ADP citrate dextrose.
- the gravitational separation of step b) is performed at a gravitational force between 175 gf to 275 gf, and even more preferably, between 180 gf and 270 gf.
- the duration of said separation is carried out for a period between 7 min to 15 min and the differential settling period is 5 min to 8 min.
- the method includes an additional step f) which consists in obtaining a fraction that replaces or recovers the separated ionic elements during the gravitational process, which must have the following physiological composition:
- the method comprises an additional step g) where the matrix is produced from the mixture of the molecular fraction and the ionic substitute in a proportion of 1 ml of molecular fraction for every 50 ⁇ of ionic substitute.
- PDGF PDGF
- EGF Epidermal growth factor
- FGF Fibroblast growth factor
- IGF Insulin-like growth factor
- VEGF Endothelial vascular growth factor
- TGF- ⁇ Vector of transforming growth ⁇
- HGF hepatocyte growth factor
- NGF nerve growth factor
- the matrix is claimed as a three-dimensional biomaterial comprising the mixture of the molecular fraction and the ionic substitute.
- the mixture of the biomaterial of the invention together with other materials or biomaterials such as lyophilized bone, bank bone and hydroxy apatite among others.
- the invention covers the combination of the matrix with at least one medicament selected from the group comprising: antibiotics, analgesics, antioxidants, recombinant molecules, cytostatics, vitamins.
- the invention also includes the regeneration kit comprising the molecular fraction obtained in steps a) to e) and the ionic substitute obtained in step f).
- the kit includes packaging, instruction manual and disposable items to perform clinically appropriate handling, such as phlebotomy tubes, multiple phlebotomy needle, element disinfectant, syringes, transfer pipettes, cut plate and a petri dish.
- the use of the disclosed matrix in various applications, among which are counted are: the regeneration of soft tissues, such as mucosa and skin; hard tissue regeneration, including bone and cartilage; epithelial regeneration and keratinization; tissue adhesion, scarring, preservation and implantation of autologous or cultured cells, reduction or elimination of post-surgical paresthesias, local hemostasis, local release and transfer of molecules and medications, bioabsorbable matrices with barrier effect (guided bone regeneration or guided periodontal regeneration), neovascularization and tissue revascularization, optimization of reimplantation of structures or tissues lost due to trauma, prosthetic osseointegration, recovery and regeneration of ligaments and tendons, biostimulation for dermal regeneration in the process of body rejuvenation, among others.
- soft tissues such as mucosa and skin
- hard tissue regeneration including bone and cartilage
- epithelial regeneration and keratinization tissue adhesion, scarring, preservation and implantation of autologous or cultured cells, reduction or elimination of post-surgical
- Figure 1 A and 1 C show the initial clinical conditions of the lesions before treatment.
- the results obtained after 30 days of the application of the CO 05-034788 membrane are shown in Figure 1 B, while the clinical results 30 days after the application of the matrix of the invention are shown in Figures 1 D .
- the regenerative process is optimal with the matrix object of the invention, compared with the results achieved with the membranes that do not complete the scar process, which is correlates with the lack of membrane three-dimensionality causing partial scarring.
- Protocol for using the matrix of the invention in bone regeneration processes together with other materials or biomaterials (lyophilized bone, bank bone, hydroxy apatite etc)
- Figure 2A and 2C show the initial clinical conditions of maxillary lesions in human before treatment.
- Figure 2E and 2G show the initial clinical conditions of femoral neck lesions in rabbits before treatment.
- Figures 2B and 2D show clear advantages in the achievements achieved by applying the matrix of the invention. While Figure 2B, CO membrane 05-034788, shows a partial bone regeneration at 6 months of treatment. Figure 2D, which shows the results obtained with the matrix of the invention, demonstrates complete, differentiated and controlled bone regeneration in its growth at 4.5 months after the treatment is applied. In the same sense are the results of figures 2F and 2H that allow to establish clear advantages in terms of tissue architecture, quality and biological organization in bone regeneration, in reduced time.
- a dose of 20 mg of doxycycline was used as part of the host modulation treatment model for periodontal disease treatment (as shown in Figure 3A).
- Figures 3B and 3D show the initial state of two patients with severe gingival retraction due to periodontal disease.
- the achievements achieved after 30 days of treatment with the matrix of the invention are shown in Figure 3C and the advances achieved in the same period with the composition disclosed in CO 05-034788 are shown in Figure 3E.
- Figure 3E shows the partial reparative effect of the composition of CO 05-034788, where the total regeneration of the interdental papillae or the total coverage of the exposed root is not achieved, while stopping in Figure 3C , where the treatment is carried out with the matrix of the invention, it is clear that at the same time the total repair of the defect is achieved, completely covering the root and completely preserving the patient's interdental papillae.
- Figure 4A shows the status of the Burn at the initial time of treatment
- Figure 4B represents the preparation of the matrix
- 4C its topical use.
- Figures 4D, 4E and 4F show the regenerative process with intervals of one week. As can be seen, after 3 weeks the healing has been complete, without showing tissue retraction.
- Figures 5A and 5C show photographs of patients in their initial stage, that is, with open lesions on the lip.
- Figure 5B and 5D we can compare the partial adherent and scarring effect by the composition disclosed in CO 05-034788 and total when the matrix of the invention is used, after 24 hours after the local application.
- a lax matrix (6C) is produced and applied to the fistula (6D) and by means of a blepharopome, the eyelid is closed and fixed by 24 hours. At the end of the period, the complete healing of the fistula (6E) can be observed.
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Abstract
L'invention concerne un procédé destiné à obtenir des matrices moléculaires régénératrices qui induisent, par signalisation cellulaire, la différentiation sélective des cellules mères mésenchymateuses présentes dans tous les tissus conjonctifs. En outre, elle concerne la matrice obtenue au moyen de ce procédé, laquelle possède les propriétés régénératrices des tissus conjonctifs durs et mous avec des utilisations tant pour des êtres humains que pour des animaux. La matrice de l'invention est utile dans de multiples applications, entre autres, pour la régénération de tissus mous, tels que les muqueuses et la peau; la régénération de tissus durs, entre autres les os et le cartilage; la régénération épithéliale et la kératinisation; l'adhésion tissulaire, la cicatrisation, la conservation et l'implantation de cellules autologues ou cultivées, la diminution ou l'élimination de parenthèses post-chirurgicales, l'hémostase locale, la libération et le transfert local de molécules et de médicaments, de matrices bioabsorbables à effet barrière (régénération soit guidée, soit périodontique guidée), la néovascularisation et la revascularisation tissulaire, l'optimisation de ré-implantation de structures ou de tissus perdus par traumatisme, oséointégration prothésique, etc.
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PCT/IB2009/055180 WO2011061561A2 (fr) | 2009-11-19 | 2009-11-19 | Procédé destiné à obtenir des matrices moléculaires régénératrices et matrices moléculaires régénératrices ainsi obtenues |
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PCT/IB2009/055180 WO2011061561A2 (fr) | 2009-11-19 | 2009-11-19 | Procédé destiné à obtenir des matrices moléculaires régénératrices et matrices moléculaires régénératrices ainsi obtenues |
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WO2011061561A3 WO2011061561A3 (fr) | 2012-08-23 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CO5570111A1 (es) * | 2005-04-13 | 2005-10-31 | Elda Restrepo | Nueva tecnica para obtener en una sola fase factores autolo- gos de crecimiento, trombina y fibrina, para ser aplicados en forma gelificada |
US20080199513A1 (en) * | 1997-06-24 | 2008-08-21 | Cascade Medical Enterprises, Llc | Systems and methods for preparing autologous fibrin glue |
ES2306655T3 (es) * | 1999-01-26 | 2008-11-16 | Eduardo Anitua Aldecoa | Composicion para la regeneracion de tejido oseo. |
-
2009
- 2009-11-19 WO PCT/IB2009/055180 patent/WO2011061561A2/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080199513A1 (en) * | 1997-06-24 | 2008-08-21 | Cascade Medical Enterprises, Llc | Systems and methods for preparing autologous fibrin glue |
ES2306655T3 (es) * | 1999-01-26 | 2008-11-16 | Eduardo Anitua Aldecoa | Composicion para la regeneracion de tejido oseo. |
CO5570111A1 (es) * | 2005-04-13 | 2005-10-31 | Elda Restrepo | Nueva tecnica para obtener en una sola fase factores autolo- gos de crecimiento, trombina y fibrina, para ser aplicados en forma gelificada |
Non-Patent Citations (2)
Title |
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DOHAN M. D. ET AL.: 'Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF).' TRENDS IN BIOTECHNOLOGY. vol. 27, no. 3, 31 January 2009, pages 158 - 167 * |
EPPLEY, B. ET AL.: 'Platelet Quantification and Growth Factor Analysis from Platelet-Rich Plasma: Implications for Wound Healing.' PLASTIC AND RECONSTRUCTION SURGERY. vol. 114, November 2004, pages 1502 - 1508 * |
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