Classifications

• • 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
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
  • A01N1/10—Preservation of living parts
  • A01N1/12—Chemical aspects of preservation
  • A01N1/122—Preservation or perfusion media
  • A01N1/124—Disinfecting agents, e.g. antimicrobials
• • 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
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
  • A61L27/3645—Connective tissue
• • 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
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
  • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
  • C12N5/06—Animal cells or tissues; Human cells or tissues
  • C12N5/0602—Vertebrate cells
  • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
• • 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
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
• • 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
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
• • 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
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

• the present invention is directed to a method for producing collagen connective tissue, the tissue thus produced and its uses. Particularly, the present invention deals with the preservation of collagen connective tissue in order to provide the structural integrity of the collagen fibers, making said tissue suitable for use in implants without immune and/or inflammatory rejection.
• the present invention has its preferred use in surgical interventions for correcting various anomalies of the human body, where a graft is particularly required.
• Patent BRP 10814523-7 B1 discloses a biocompatible composite implant and a method for forming the same, comprising a framework of reticulated collagen tissue processed without glutaraldehyde and an elongated member, in which these are kept in contact with each other along the length of the frame.
• the penis As well known in the branches of medicine, the penis, the male sexual organ, when in a state of erection, in most men, presents some degree of curvature. Deviations of less than 20 degrees in the axis of the penis are considered normal and, in general, do not harm, for example, penetration, thus not causing problems for a man's sex life. However, deviations greater than 20 degrees are considered pathological and affect at least 10% of men around the world. Depending on the degree of curvature, penetration can become difficult or even impossible. Exaggerated penile curvature can be congenital or caused by Peyronie's disease. Although this condition is benign and poses no risk to the patient's health, it can bring serious problems to the patient's sexual and psychological life.
• the penis is an organ that has the ability to increase in size and become erectile when the man is sexually excited. This is possible due to its anatomical structure, formed in the center by a bundle of tissue called the corpus spongiosum, through which the urethra passes, and on the sides by two bundles of tissue called the corpora cavernosa. These tissues have internal spaces that fill with blood when the man is sexually excited, causing them to increase in size and become more rigid, in order to allow penetration and, consequently, the sexual act. These tissues are covered externally by a compliant tissue called the tunica albuginea.
• Peyronie's disease is more common in men over 40 years of age and is usually caused by micro-trauma to the tunica albuginea that may occur throughout the patient's sexual life.
• fibrous tissue can develop in the tunica albuginea, in the form of plaques or nodules that reduce the compliance of the tunica in the area of fibrosis. Due to this loss of compliance in the area of fibrosis, when the penis becomes erect, the corpora cavernosa cannot fully distend and the penis becomes curved.
• tissue graft which may be of the autologous or autograft type, where tissue is transplanted from one part of the body to another of the same individual ; (b) isograft, allograft or homologous graft, where tissue from the body of another animal of the same species is transplanted, but with a different genotype from the individual; or (c) xenograft or heterologous graft, where body tissue is transplanted between animals of different species.
• tissue graft which may be of the autologous or autograft type, where tissue is transplanted from one part of the body to another of the same individual ; (b) isograft, allograft or homologous graft, where tissue from the body of another animal of the same species is transplanted, but with a different genotype from the individual; or (c) xenograft or heterologous graft, where body tissue is transplanted between animals of different species.
• the tissue used for the graft must have some special characteristics, which are difficult to find, especially in heterologous tissues available on the market. Among these characteristics, the main ones are: the tissue used for the graft must have compliance similar to that of the tunica albuginea, otherwise the problem will not be solved; the tissue used for the graft must be biocompatible and not cause allergic, inflammatory reactions or rejection; the tissue used for the graft must not undergo calcification; the fabric used for the graft must be able to allow the growth of the patient's own cells on it, promoting biointegration; and tissue used for the graft must not undergo retraction after surgery, otherwise the problem will not be resolved.
• the method disclosed by document US 7,008,763 B2 is based on the use of glutaraldehyde-free preservative solution, comprising a saline solution, a stabilizing solution, a solution composed of polyglycol, a salt, a phosphate buffer and an oxidizing agent.
• BMF maxillofacial reconstruction
• biomaterial For the use of the biomaterial to be successful, it must be bio-tolerated, that is, not cause local or systemic damage, not be toxic, carcinogenic or radioactive. Furthermore, an ideal biomaterial must be manufacturable, sterilizable and stable during application or implantation. Studies report that the use of bioabsorbable materials has advantages over non-absorbable ones, as they avoid problems with migration, extrusion and late infection.
• the method for producing preserved collagen connective tissue from an animal donor source comprises the following steps: a) after removing the donor, trimming the collagen connective tissue in a buffered solution; b) washing the connective tissue with the same buffered solution c) stabilizing the tissue in a 50% ethanol solution; d) treating the tissue with a polyethylene glycol solution; e) wash and preserve the tissue in 50% ethanol; f) sterilize the tissue with a solution of 50% ethanol and 1.5% hydrogen peroxide (H2O2); and g) store the tissue in a 50% ethanol and indomethacin solution.
• the buffered solution according to the present invention is a mixture of phosphate buffer solution, composed of monobasic sodium phosphate (NaH 2 PO 4 ) 0.1% and dibasic sodium phosphate (NaH 2 PO 4 ) 0.6% and sodium chloride solution (NaCl) 0.9%, and the pH of the solution is physiological, preferably in the range of 7.3 to 7.5 and the temperature must be within a range of 5° C to 15°C. Still preferably, about 500 ml of the buffered solution are used for washing each piece of collagen connective tissue, using about 56 grams per liter of buffered solution.
• Stabilization of collagen connective tissue should be performed with 50% ethanol at a temperature in the range between 2°C and 10°C.
• the stabilized tissue is then treated with a polyethylene glycol solution comprising a mixture of polyethylene glycol 6% v/v, sodium chloride (NaCl) 32% v/v, phosphate buffer solution 13% v/v, and hydrogen peroxide (H2O2) 2% v/v, the temperature being controlled within a range of 2°C to 8°C.
• a polyethylene glycol solution comprising a mixture of polyethylene glycol 6% v/v, sodium chloride (NaCl) 32% v/v, phosphate buffer solution 13% v/v, and hydrogen peroxide (H2O2) 2% v/v, the temperature being controlled within a range of 2°C to 8°C.
• the tissue thus stabilized is then washed and preserved in a 50% ethanol solution at a temperature of around 25°C, and subsequently sterilized with a 50% ethanol solution and 1.5% hydrogen peroxide (H2O2) .
• the collagenous connective tissue is stored ready for use in a solution of 50% v/v ethanol and about 0.05% v/v indomethacin for a period of up to 2 years.
• the steps of washing with the buffered solution, stabilization with 50% ethanol solution and washing and conservation of collagen connective tissue with 50% ethanol solution are advantageously repeated from 3 to 6 times, preferably the washing step of the fabric is repeated 5 to 6 times, stabilization is repeated 3 times and the washing and conservation step is repeated 3 to 5 times.
• the immersion time varies from 24 to 96 hours, with the stabilization stage preferably being carried out for 24 hours per repetition, the treatment stage for 96 hours and the sterilization step for 24 hours.
• a scale of 1 to 5 was used for subjective assessment of the satisfaction of individuals with curvature correction. Four patients (57%) were satisfied (4/5 on the scale) and three patients (43%) were very satisfied (5/5 on the scale). on the scale). A satisfactory correction of the penile curvature was obtained in 89% of the cases and only one patient, who had a complex penile curvature in 2 axes, remained with a significant penile curvature in one of the axes (approximately 60°). Despite this, this patient does not report difficulties in maintaining penetrative sex. No significant complications were identified in the 7 patients reassessed so far, according to the Clavien Dindo scale.
• the graft allows the growth of the patient's own structural cells over it, promoting biointegration in such a way that the graft starts to exhibit functional and biological characteristics similar to the tissue in which it was grafted, such as vascularization, innervation and incorporation of cells of collagen and elastin, to the point that after some time it is no longer possible to differentiate the grafted tissue from the native tissue; - the tissue presents elasticity, flexibility and complacency, even allowing the growth of the graft when necessary to adapt to anatomical alterations suffered by the patient;
• the graft produced by the method of the present invention does not undergo retraction after surgery.
• the investigated graft was an aldehyde-free bovine pericardium membrane manufactured by the company Labcor Laboratórios Ltda. (-MG count), produced by the method described by the present invention.
• the product was manufactured using non-aldehyde technology.
• a first study involving preserved non-aldehyde collagen connective tissue was performed with a female patient, 36 years old, with a history of ankylosis in the left temporomandibular joint (TMJ) (E) associated with dentofacial deformity.
• the patient had been submitted to three surgeries, among which a procedure for correction of bone distraction in the mandible and another for the release of the L TMJ with implantation of silicone prosthesis and ostectomy of the head of the L mandible.
• the patient had scars resulting from the surgeries anterior teeth, severe limitation of mouth opening, poor state of oral hygiene with multiple caries, periodontal disease advanced, impacted teeth in the mandible and cystic-looking horns in the mandible and maxilla. He also showed an infectious condition with an abscess on the left face, where the prosthesis was exposed.
• Aldehyde-free bovine pericardium membrane graft was employed for interposition between the bone surfaces and closure of the fistula. Said graft was sutured to adjacent tissues under constant tension to keep it immobile. Postoperative tomography indicated satisfactory position of the graft and one week after the surgical procedure, the patient already showed improvement in mouth opening and closing, previously limited. The patient did not present any inflammatory reaction or graft rejection, even after six months of follow-up, thus demonstrating the total feasibility of using the preserved non-aldehyde collagen connective tissue graft for facial reconstruction.
• a second study involving preserved non-aldehyde collagen connective tissue was performed with a female patient, 69 years old, with a history of multiple facial fractures for at least twenty years, presence of silicone prosthesis displaced from the orbital floor and process infection in the L orbit with a fistula in the inner part of the L lower eyelid.
• the prosthesis produced pressure on the eyeball, causing diplopia and “blurred vision”.
• the correction was performed under general anesthesia with an infraorbital L access.
• the bone gap in the lower rim of the L orbit was adjusted using a titanium miniplate of approximately 1.5 mm with fixation by means of two screws with a diameter of about 1.5 mm.
• the preserved non-aldehyde collagen connective tissue graft was placed on the orbital floor to occupy the space resulting from the absence of the prosthesis (which occupied the region, supporting the eye) and to correct the orbital deformity.
• the graft was fixed to the plate and adjacent tissues, already occluding the fistula.
• the patient also had a silicone orthosis on the left face that caused a fistula in the inner region of the lower eyelid, externalizing part of the orthosis and compressing the eyeball.
• a chronic infectious/inflammatory process generated a constant secretion in the left eye.
• An infraorbital incision was then made using an expression line below the eyelid so that the access was wider and preserved the eyelid, allowing the removal of the orthosis .
• After removal of the orthosis we observed a displacement of the left eye that invaded the maxillary sinus area, in addition to a bone space on the lower edge of the left orbit that allowed such displacement.
• the tissues were divulsed and the bone remnants of the left orbital floor were exposed, also limiting the space that originally belonged to the left maxillary sinus. since the entire bone structure had been modified for decades since the facial trauma.
• a third study involving preserved non-aldehyde collagen connective tissue was performed on a female patient, 76 years old, with a periodontal lesion in the region of teeth 43, 44 and 45.
• the patient had undergone a curettage and biomaterial graft, as indicated by imaging studies.
• the tests also revealed a fistula in the buccal region of tooth 45 and a lingual increase in the region of teeth 43, 44 and 45. Upon palpation, the region had a hardened appearance.
• the preserved collagen connective tissue was sutured to the lingual tissues isolating the ducts.
• a bone graft was made with biomaterial and the preserved collagen connective tissue was folded over the graft to serve as a barrier.
• the preserved collagen connective tissue was sutured in tension over the graft.
• the lesion was diagnosed as an ameloblastoma, and reconstruction through guided bone regeneration (GBR) was considered to enable visualization and removal of the lesion.
• GBR guided bone regeneration
• Preserved collagenous connective tissue was used due to the large extent of the repair to be performed and the need for an extensive barrier that is not available on the market.
• the choice of preserved collagen connective tissue was also based on the possibility of handling and fixing the membrane to local tissues. There was a small exposure of collagen connective tissue preserved in the postoperative period, which in no way compromised the results.
• a fourth study involving preserved non-aldehyde collagen connective tissue was performed on a male patient, 36 years old, who had lost both lower central incisors.
• the preserved collagenous connective tissue was used as a barrier for bone grafting and as a substitute for connective tissue to improve gingival recession! in the lower incisors, in order to allow a future rehabilitation with implants.
• the medical literature indicates guided bone regeneration (ROG) and the use of connective tissue grafts due to the gingival profile! patient's end. Therefore, the case required a bone graft, a graft barrier, and a connective tissue graft.
• Such demands added to the large extent of the defect, guided the choice of preserved collagen connective tissue, which could function as a barrier and connective tissue replacement, improving the gingival profile.
• a fifth study involving preserved non-aldehyde collagen connective tissue was performed on a female patient, 32 years old, indicated for implant rehabilitation due to the loss of tooth 44, with consequent vestibular dehiscence.
• the buccally preserved collagen connective tissue was used to gain gingival profile, as the patient was opposed to removing connective tissue from a second surgical site.
• the preserved collagen connective tissue was used as tissue graft and fixed by suture. The ones after a month of the procedure showed a perfect correction.
• a sixth study involving preserved non-aldehyde collagenous connective tissue was performed on a female patient, 62 years old, with root fracture in tooth 34 and buccal bone loss. After removal of the residual root, an implant was placed in place. Bone loss was compensated with a biomaterial graft and the preserved collagen connective tissue acted as a barrier to prevent gingival recession.
• An immediate load implant was installed in the region of the lower premolar E. Due to buccal bone loss, guided bone regeneration (ROG) was chosen. However, the soft tissues were insufficient to cover the bone graft, because the root fracture and the chronic inflammatory process in the region had caused gingival recession. Preserved collagen connective tissue was chosen as this would serve as a barrier to bone regeneration and allow the gain of gingival tissue. The results after two months, with the prosthesis installed over the implant, were excellent.
• a seventh study involving preserved non-aldehyde collagen connective tissue was performed in a female patient, 37 years old, smoker, with poor oral hygiene, showing destruction of several crowns of the remaining teeth and periodontal disease. Previously, she had undergone multiple extractions, both in the mandible and maxilla, for the installation of Morse taper dental implants with the intention of rehabilitation with protocol-type prostheses in both dental arches.
• the preserved collagen connective tissue was accommodated over the buccal bone tissue of the maxilla as if it were the periosteum.
• the suture was made with non-absorbable thread and removed in 15 days.
• An additional reason for choosing preserved collagenous connective tissue was the need to remove the surroundings of the patient's teeth, due to periodontal disease and smoking, which resulted in insufficient flap to cover the surroundings of the implants.
• the preserved collagenous connective tissue also allowed gain of buccal tissue in the maxilla, improving the emergence profile of the prosthesis and posture of the upper lip.
• the bone pocket on the D revealed exposure of the inferior alveolar plexus with an anterior lesion on the D.
• a bone graft with biomaterial was implanted.
• the preserved collagen connective tissue was used as a barrier in the GBR, having been sutured lingually and buccally so that it was tense over the bone graft.
• Diagnosis keratocysts. Image exams after the surgical procedure indicated good absorption and patient recovery. The result after six months was complete recovery of the injuries.
• a ninth study involving preserved non-aldehyde collagen connective tissue was performed on a male patient, 44 years old, who exhibited complications from orthognathic surgery.
• the patient had been referred by the orthodontist for extraction of element 47, which was compromised due to the postoperative fracture of the first surgery.
• the extraction of the tooth presented challenges, since the tissues in the region were without elasticity and there was intense fibrosis due to the previous infectious process.
• the preserved collagenous connective tissue was used in tooth removal to ensure that plaque exposure was not aggravated and that there was no severe tissue retraction, which would result in bone exposure after extraction.
• the preserved collagen connective tissue was used to cover the remaining bone after tooth extraction.
• the graft was sutured lingually, bent over the exposed bone, and again sutured buccally, keeping it tense over the covered area.
• the preserved and stabilized collagen connective tissue can be used in several applications of facial recovery, since being a non-aldehyde preserved biomaterial, it showed wide versatility and produced results above expectations in the short and long term, also avoiding the extraction of autogenous flaps in some situations.
• the present invention also contemplates the collagen connective tissue preserved by the method described above, its uses in repair surgery with collagen connective tissue in any region or organ of the human body, as well as a surgical kit comprising the preserved collagen connective tissue and stabilized.

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• 2021
  • 2021-09-02 BR BR102021017465-0A patent/BR102021017465A2/pt not_active Application Discontinuation
• 2022
  • 2022-09-01 US US18/688,672 patent/US20240373841A1/en active Pending
  • 2022-09-01 EP EP22862452.4A patent/EP4397299A4/en active Pending
  • 2022-09-01 JP JP2024514372A patent/JP2024531568A/ja active Pending
  • 2022-09-01 WO PCT/BR2022/050348 patent/WO2023028681A1/pt not_active Ceased

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