63 results about "Cartilage Matrix" patented technology

The invention belongs to the technical field of microbial fermentation, and particularly relates to lactobacillus rhamnosus capable of maintaining bone health and improving local joint inflammation and a metagen and application of the lactobacillus rhamnosus. According to the invention, the probiotic NKU ML1-2 is subjected to fermentation culture, such that a post-generation product is prepared. Results of embodiments prove that the metagen product can enhance the oxidation resistance of cartilage and osteoblasts and promote the synthesis of anti-inflammatory factors and cartilage matrixes (type II collagen and proteoglycan), and has the potential of relieving oxidative stress and inflammatory response of local joints, relieving joint inflammation and delaying cartilage destruction. The prepared metagen product is high in safety and good in stability, and can be applied to preparation of medicines for preventing and / or treating osteoarthritis; the metagen product can also be used for promoting bone health, enhancing the antioxidant capacity of osteoblasts and / or chondrocytes, promoting osteoblast activity and / or promoting calcium absorption and fixation, and a new solution is provided for joint health management.

The invention discloses a biphasic hydrogel scaffold of a bionic bone cartilage matrix as well as a preparation method and application of the biphasic hydrogel scaffold, and belongs to the technical field of tissue engineering. The biphasic hydrogel scaffold of the bionic bone cartilage matrix provided by the invention comprises a hard bone matrix phase and a cartilage matrix phase. Wherein hard chitosan hydrogel with a porous structure is used as a hard bone matrix phase, and soft chitosan hydrogel is used as a cartilage matrix phase. The biphase hydrogel with the asymmetric matrix stiffness and the biochemical microenvironment can effectively release active substances in a controlled mode, the release period exceeds 21 days, the time requirement for osteochondral repair is met, and lasting support is provided for proliferation and differentiation of cells. Meanwhile, the biphase hydrogel provided by the invention has good biological safety, two matrix phases have different mechanical properties, the biphase hydrogel adapts to in-vivo complex physiological and mechanical environments, the fate of stem cells can be directionally regulated and controlled, synchronous regeneration and repair of osteochondral tissues are realized, and the biphase hydrogel has a wide application prospect.

Aiming at the challenge of osteochondral defect repair, the invention provides a preparation method of a fiber-reinforced self-repairing hydrogel scaffold (SBPS). According to the method, phenylboronic acid modified sodium alginate, polyvinyl alcohol and fibroin nanofibers rich in beta-Sheet are utilized to form the hydrogel through dynamic boric acid ester bonds and hydrogen bonds. The SBPS hydrogel loaded with PDGF-BB is combined with the nanosheet containing LDH / ChS / TGF-beta3, so that multi-dimensional synergy of mechanical strengthening, sequential drug release (PDGF-BB is released in an early stage and TGF-beta3 / Mg < 2 + > is released in a later stage), ROS removal and endogenous repair is realized. The Mg < 2 + > concentration gradient effect further assists staged regulation (vascularized bone regeneration-cartilage matrix synthesis), and breaks through the limitation of a single factor. Experiments prove that the scaffold can effectively drive angiogenesis, stem cell recruitment and cartilage / bone differentiation in vivo and in vitro, and finally osteochondral regeneration with structure-function matching is achieved.

The invention provides a nanogel for rapid permeation of articular cartilage and responsive release of a growth factor, which is prepared by polymerizing a peptide fragment which can be cut by a substance (mainly enzyme) which can be specifically expressed on the surface of osteoarthritis cells or secreted into a matrix with the growth factor, an acrylamide monomer and a cationic micromolecule monomer. Unreacted monomer molecules are filtered out through an ultrafiltration tube or other filtering systems, so that the nanogel which can rapidly permeate into the deep part of articular cartilage and can be recognized and cut by enzyme highly expressed on the surface of osteoarthritis cells or secreted enzyme to release growth factors is prepared, and the effect of the growth factors can be more effectively exerted; the nanogel has strong cartilage infiltration capacity, can completely infiltrate cartilage with the thickness of 1mm within less than 3 days, can be cut by MT1-MMP protein specifically expressed on the surfaces of osteoarthritis cells, releases growth factors, is specifically combined with growth factor receptors on the surfaces of cartilage cells, and activates downstream signal channels, so that the proliferation of the cartilage cells is promoted, and the cartilage cell proliferation rate is increased. The cartilage matrix secretion is promoted, so that the cartilage matrix thickening effect is realized, and the osteoarthritis is prevented and treated.

The gadolinium-based cationic polymer contrast agent is synthesized by chelating a cationic polymer and gadolinium ions, has high biological safety and can be used for cartilage imaging. The prepared contrast agent adopts an articular cavity direct injection method, so that the imaging effect is improved, and the contrast dosage is reduced. When the cartilage activity is normal, the content of glycosaminoglycan in the matrix is rich, and when the cartilage is inactivated or the activity is reduced, the content of glycosaminoglycan in the matrix is obviously reduced. The gadolinium-based cationic polymer contrast agent is combined with negatively charged glycosaminoglycan in a cartilage matrix through the charge effect. The gadolinium-based cationic polymer contrast agent can be used for noninvasive and quantitative evaluation of cartilage activity in nuclear magnetic resonance imaging, especially cartilage activity and stability in transplantation.

The invention provides a pharmaceutical composition for bone joints as well as a preparation method and application of the pharmaceutical composition. The pharmaceutical composition is prepared from the following components in parts by weight: 20 to 2000 parts of N-acetylglucosamine and 10 to 1000 parts of non-denatured type II collagen. In the compound composition of the N-acetylglucosamine and the non-denatured type II collagen, the two core components play a complementary role: the N-acetylglucosamine is focused on promoting synthesis of a cartilage matrix and provides a material basis for cartilage repair; the non-denatured type II collagen reduces damage of autoimmune response to cartilage through immunoregulation, the non-denatured type II collagen and the non-denatured type II collagen have a synergistic effect, the symptoms such as arthralgia and swelling can be relieved, the joint structure can be improved from the double angles of repairing and protecting, and particularly the treatment effect on patients with severe osteoarthritis is remarkably superior to that of a single-component preparation; and an innovative and efficient choice is provided for the treatment of osteoarticular diseases.

The invention provides application of apoptotic cell pretreated macrophages in preparation of an osteoarthritis treatment preparation, a cell preparation and a preparation method, and relates to the technical field of biomedicine.In the embodiment of the invention, based on a mouse development model and an osteoarthritis (OA) model, it is found that in the area away from the cartilage surface, the apoptotic cell pretreated macrophages are subjected to apoptotic cell pretreatment, and the apoptotic cell pretreated macrophages are subjected to apoptotic cell pretreatment in the area away from the cartilage surface; in the macrophages, the content of the interment-related LAMP1 protein is obviously higher than that of the macrophages close to the cartilage surface area, and the expression results of TGF-beta 1 and LRG1 are respectively opposite and consistent with those of the LAMP1. The invention also finds that after the chemotactic effect of apoptotic cells on macrophages is weakened, the cellular burial effect is limited, and the cartilage matrix development disorder is caused. Based on development process inspiration, the invention provides a treatment strategy: bone marrow-derived macrophages pretreated by apoptotic cells are injected into articular cavities, and a good cartilage regeneration treatment effect can be achieved in a mouse arthritis model. In addition, the bone marrow-derived macrophages pretreated by apoptotic cells can still express TGF-beta1 after being injected into the body for 3 days, so that the effect of continuously promoting cartilage regeneration is achieved.

The invention relates to the technical field of medicines, and provides application of pulsatilla saponin B4 in preparation of a medicine for treating osteoarthritis. The pulsatilla saponin B4 can obviously promote the expression of SOX9, which is an important cartilage specific transcription factor, and inhibit the expression of matrix metalloproteinase 13 and disintegrin and metalloproteinase 5 with platelet reaction protein motifs at the same time, thereby finally relieving the degradation of extracellular cartilage matrixes such as II-type collagen and aggregation proteoglycan. Therefore, the pulsatilla saponin B4 can inhibit cartilage degeneration and improve cartilage extracellular matrix metabolic disorder. After the pulsatilla saponin B4 is injected into the abdominal cavity of a mouse with osteoarthritis, the progress of the osteoarthritis is effectively relieved, the side effect is relatively small, and no obvious injury is caused to main organs. The pulsatilla saponin B4 is applied to treatment of osteoarthritis, new application of the pulsatilla saponin B4 is developed, and a new choice is provided for preparation of the medicine for treating osteoarthritis.

The invention discloses a parasitic loranthus exosome-like nano vesicle and application thereof in preparation of a medicine for treating temporomandibular joint osteoarthritis. The taxillus sutchuenensis exosome-like nano-vesicles are prepared by combining a differential ultracentrifugation method with an ultrafiltration method. Researches show that the taxillus sutchuenensis exosome-like nano-vesicles can treat temporomandibular joint osteoarthritis through the following aspects: 1) an anti-inflammatory function: effectively reducing expression of inflammatory factors; 2) a cartilage degeneration inhibition function: blocking a cartilage matrix degradation pathway, and slowing down cartilage tissue damage; the taxillus sutchuenensis exosome-like nano-vesicles have the advantages that the taxillus sutchuenensis exosome-like nano-vesicles have obvious protection and repair effects on relieving temporal-mandibular joint osteoarthritis related bone and cartilage damage, and accordingly the taxillus sutchuenensis exosome-like nano-vesicles have good application prospects.

A method for modeling temporomandibular joint osteoarthritis, 6-week-old rats are selected, the rats are confirmed to have entered an anesthetized state before surgery, the rat's mandibular incisors are first checked and confirmed to be normal, the first arm of the device is sleeved on one side of the mandibular incisor, and the palatal side of the maxillary incisor is made to touch the slope surface of the second arm of the device, the device is checked and confirmed to not affect the rat's mandibular movement and occlusion, not significantly raise the bite, have no early contact, and the upper and lower jaw relationship is relatively stable; the device and the mandibular incisor sleeved with the device are fixed; then the rat is put back into the cage, and soft food or powdered feed is given after waking up; the device is removed after being fed for 8 weeks or more. It is verified that the condylar process of the rat changes significantly, the overall condylar process is significantly reduced, the subchondral bone is destroyed, and the expression of the cartilage matrix is also reduced. Thus, a TMJOA rat model exhibiting mandibular retrusion is formed.

The present invention provides a cartilage matrix having a high decellularization level and a low glycosaminoglycan (GAG) content. The cartilage matrix exhibits desirable characteristics, for example, cohesiveness, tackiness and malleability, for use in cartilage repair. Also provided is a method of preparing the cartilage matrix, comprising decellularizing a cartilage to generate a decellularized cartilage, and deglycosylating the decellularized cartilage.

The invention discloses application of rebaudioside B in preparation of a medicine for preventing and treating metabolism-related osteoarthritis, and belongs to the technical field of biological medicine. Animal experiments prove that the application of the natural micromolecular monomer rebaudioside B in preventing and treating osteoarthritis induced by high fat diet shows that the rebaudioside B can realize a cartilage protection effect by improving lipid deposition, regulating inflammatory response and promoting cartilage matrix synthesis; the method is suitable for intervention and prevention and treatment of metabolism-related osteoarticular diseases. The invention provides a set of intervention scheme with clear structure, multi-target action, clear mechanism and controllable path for the prevention and treatment of metabolism-related osteoarthritis, and provides a scientific basis for the application of rebaudioside B in the prevention and treatment of metabolism-related osteoarthritis.

An object is to provide a joint function-improving composition which is useful for prevention or treatment of various arthropathies such as osteoarthritis including knee osteoarthritis as a typical example and rheumatoid arthritis because the composition has an action of promoting growth of chondrocytes and an action of suppressing the production of an inflammation factor, a cartilage matrix degradation factor, a pain factor or a neuronal outgrowth factor by synoviocytes and to provide a joint function-improving product containing the composition such as a food or a drink, feed and a medicine. A joint function-improving composition containing bacterial cells and / or a culture of a bacterium belonging to genera Lactobacillus, Lactococcus, Streptococcus or Bifidobacterium and a joint function-improving agent, a joint function-improving food or drink, a joint function-improving nutritional composition, joint function-improving feed or a joint function-improving pharmaceutical agent which is characterized by containing the joint function-improving composition.

The invention belongs to the technical field of biological medicine, and discloses application of miRNA Let-7a-5p in a medicine for promoting cartilage formation, the invention provides the effect of miRNA let-7a-5p in cartilage formation / generation for the first time, and experiments prove that miRNA let-7a-5p can remarkably promote cartilage cell proliferation, enhance the activity of cartilage cells and remarkably improve matrix secretion of cartilage cells, so that the effect of promoting cartilage formation / generation is achieved. The expression of type II collagen is increased (the type II collagen is the main component of the cartilage matrix). Meanwhile, the miRNA let-7a-5p can also regulate other genes (such as NBL1 and DUSP7 genes) to inhibit cartilage ossification, and is expected to be applied to cartilage injury repair and osteoarthritis treatment, cartilage regeneration promotion and cartilage injury repair.

The present disclosure relates to a method of treating arthritis by targeting Tankyrase. The methods according to the present disclosure can be advantageously used for regeneration of cartilage tissue and for treating osteoarthritis by maximizing the matrix synthesis in cartilage by inhibition of Tankyrase and regulation of other proteins related therewith.

The application discloses a kind of for repairing cartilage decellularized cartilage matrix support and apoptotic corpuscle composition and its preparation method, composition includes: microporous support, support includes decellularized cartilage outer matrix and crosslinked organic polymer;Apoptotic corpuscle, apoptotic corpuscle exists in microporous support;Wherein, based on the volume 3.14mm 3 Microporous support, 0.01-0.02ug of apoptotic corpuscle is included.The combined support of the application can improve the activity of apoptotic corpuscle, prolong the action time of apoptotic corpuscle, achieve the effect of slow release, also can regulate joint cavity microenvironment, effectively promote joint cartilage repair, improve the repair effect of loss cartilage, avoid the security risks brought by traditional exogenous cell transplantation.

The application relates to an anti-inflammatory and cartilage regeneration promoting material, a preparation method and application thereof, and belongs to the technical field of biomedical materials. The anti-inflammatory and cartilage regeneration promoting material comprises a PLGA (50:50) polymer material, and a huperzine A derivative dimer loaded on the PLGA (50:50) polymer material through 3D printing. The application also provides the use of the anti-inflammatory and cartilage regeneration promoting material in the preparation of anti-inflammatory, cartilage protection or cartilage regeneration promoting drugs. The PLGA / A10E scaffold has good biocompatibility, the PLGA / A10E scaffold degradation release liquid can effectively promote the differentiation of cartilage precursor cells into cartilage, and increase the formation of cartilage collagen matrix and cartilage proteoglycan. The in-vitro degradation liquid of the PLGA / A10E scaffold can promote the expression of SOX9 under non-inflammatory conditions; under LPS-mediated inflammatory conditions, the expression of MMP-13 can be inhibited, thereby promoting the synthesis of cartilage matrix and inhibiting the degradation of cartilage matrix.

A pharmaceutical compositions includes GLP-1 and GLP-1 analogues inducing an anabolic stimulation of chondrocytes and a decreasing in chondrocyte catabolic including a decrease in cartilage matrix loss and cartilage degeneration for use in the treatment of cartilage disease. The composition induces cartilage regeneration and anabolic stimulation of chondrocytes, including chondrocyte proliferation and / or stem cell differentiation into chondrocytes.

The invention discloses a mesenchymal stem cell compound preparation for treating cartilage injury, and belongs to the technical field of cell biology. The composite preparation consists of human umbilical cord mesenchymal stem cells (hUC-MSC) subjected to specific pretreatment and a pharmaceutical carrier. The pretreatment method sequentially comprises the following steps: carrying out low-oxygen pretreatment on the hUC-MSC; then, carrying out pretreatment on a ferroptosis inhibitor Ferrostatin-1 under a low-oxygen condition; and finally, carrying out icariin pretreatment under a normal oxygen condition. The unique triple pretreatment strategy generates a remarkable synergistic effect, and can greatly improve the survival rate and the function maintenance capability of the hUC-MSC in the cartilage injury inflammatory microenvironment. Experimental results prove that the preparation can significantly inhibit collagen degradation and promote cartilage matrix regeneration, and the treatment efficiency of stem cell transplantation and the repair effect of cartilage injury are effectively improved.

The invention provides injectable hyaluronic acid hydrogel based on dynamic chemical bonds as well as a preparation method, application and a sol-gel conversion method of the injectable hyaluronic acid hydrogel, and belongs to the technical field of hydrogel. The preparation method comprises the following steps: oxidizing and modifying hyaluronic acid by adopting sodium periodate to obtain formylation modified hyaluronic acid, and carrying out Schiff base reaction on 3, 3 '-dithiodipropionyl hydrazine serving as a cross-linking agent and the formylation modified hyaluronic acid to prepare the injectable hyaluronic acid hydrogel. The HA-SS hydrogel provided by the invention not only has controllable gelation time, but also has excellent deformation resilience, elastic property and good biocompatibility, and can effectively simulate the structure and function of proteoglycan in a cartilage matrix. Due to the existence of the acylhydrazone bond and the disulfide bond, the injectable hyaluronic acid hydrogel based on the dynamic chemical bond has good rapid self-healing and pH / redox dual response performance.

The invention relates to the technical field of gene engineering, particularly discloses application of an NSUN2 gene in preparation of a product for diagnosing or treating osteoarthritis, and has the technical key points that the invention reveals that the NSUN2 has a potential value of serving as a clinical diagnosis biomarker; meanwhile, by knockdown and overexpression of the NSUN2 and detection of senescence and cartilage matrix synthesis and catabolism related indexes in cartilage cells, the invention finds that the NSUN2 can inhibit synthesis and secretion of cartilage matrix and promote cartilage senescence, and the increase of the NSUN2 is an important factor causing osteoarthritis, which indicates that the NSUN2 is expected to be used as a target to treat osteoarthritis.

The invention provides a tribenzoyl substituted vakognavine type diterpenoid alkaloid, a preparation method and application of the tribenzoyl substituted vakognavine type diterpenoid alkaloid, and a pharmaceutical composition. After rats are treated by the tribenzoyl substituted vakognavine type diterpenoid alkaloid provided by the invention, the quality reduction trend is obviously relieved, and the foot swelling degree and the arthritis score are obviously reduced; bone loss induced by AIA can be effectively inhibited, and the structural integrity of bone trabecula is protected; cartilage matrix degradation can be inhibited, and cartilage erosion damage is relieved; the anti-inflammatory effect can be achieved by inhibiting the expression of key proinflammatory factors in bone tissues.

This invention provides a stress-triggered selective targeting hydrogel microsphere, its preparation method, and its application, belonging to the field of biomedical technology. The core of this invention is the "stress-triggered charge reversal" mechanism. It utilizes the interaction between weakly cross-linked disulfide bonds broken under stress and "charge reversal" messenger molecules to achieve "charge reversal" of nanoparticles under stress. A dual-network hydrogel microsphere system is prepared using microfluidic technology to achieve bearing lubrication and stress relaxation within the joint cavity. Stress-triggered charge reversal is achieved at stress-overloaded cartilage lesions, imparting a positive charge to the drug-loaded nanoparticles within the hydrogel microspheres. This significantly enhances the ability of the drug-loaded nanoparticles to penetrate deep into the cartilage matrix and target chondrocytes for drug release under the guidance of the charge. This enables the selective and targeted release of appropriate drug concentrations to deep-seated chondrocytes in pathological microenvironments induced by different stress intensities, achieving highly effective and low-toxicity treatment of osteoarthritis.

The invention discloses an antler plate oligopeptide as well as a preparation method and application thereof, and relates to the technical field of bioactive peptides. The preparation method comprises the following steps: extracting an antler plate protein crude extract by taking antler plates as a raw material, preparing short peptides with antler plate molecular weight of less than 3k through pepsin and trypsin hydrolysis, and performing Sephadex G-15 gel chromatography to obtain the antler plate short peptides. The prepared antler plate oligopeptide is low in molecular weight and high in hydrophobicity, easily penetrates through a biological membrane barrier to reach an in-vivo effective part, fully plays the biological activity effect of small molecule peptide, can effectively promote C28 / I2 cartilage cell proliferation, can increase the expression of osteoarthritis related phenotype protein Collagen II in an in-vitro model, can reduce the expression of MMP3, MMP13 and ADAMTS-5, and can be used for treating osteoarthritis. Meanwhile, cartilage matrix degradation in an osteoarthritis rat model is inhibited, cartilage injury is improved, and inflammatory response induced by osteoarthritis is reduced.

The invention belongs to the technical field of biological medicine, and particularly relates to a preparation method and application of an amniotic fluid active complex. According to the method, inherent physical and chemical differences of different components in amniotic fluid are utilized, through a series of physical steps, the components are firstly and mildly grouped and enriched according to categories, and then the components are guided to be self-assembled again under controllable conditions to form a composite particle with a compact structure. The natural aggregation state of active ingredients in a living body before secretion or action is simulated, so that the multi-element active ingredients which naturally coexist and interact in amniotic fluid are efficiently captured and transferred as a complete functional unit, the natural ingredient spectrum is not damaged, and the original advanced structure and function are not lost. The invention provides application of an amniotic fluid active complex (RSC) in treating or preventing joint diseases or symptoms. The RSC has obvious effects in promoting cartilage matrix synthesis, inhibiting moderate and mild osteoarthritis and relieving pain.

This invention discloses a chitosan-based lidocaine formulation for intra-articular use and its preparation method. Belonging to the field of pharmaceutical formulation technology, the formulation is prepared from chitosan, carboxymethyl chitosan, lidocaine, chitosan-PNIPAM microspheres, sulfated trehalose, and excipients. The chitosan-PNIPAM used in this invention exhibits dual temperature and pH response. With temperature changes, PNIPAM possesses both hydrophobic contractile and hydrophilic swelling states, thereby controlling the lidocaine release rate. Simultaneously, when the pH decreases, chitosan repels PNIPAM, further disintegrating the microspheres to release the drug, thus achieving targeted analgesia. Sulfated trehalose, as a cartilage matrix synthesis promoter, can activate intracellular signaling pathways in chondrocytes, promoting the synthesis of type II collagen and proteoglycans. Simultaneously, the sulfate groups can form electrostatic complexes with the amino groups of chitosan, enhancing drug retention. The formulation of this invention can inhibit synovial cells, release cytokines, and synergistically with carboxymethyl chitosan, increase the inhibition rate of inflammatory factors by 40%-50%.

The invention provides Haitesan type diterpenoid alkaloid as well as a preparation method, application and a pharmaceutical composition thereof. After rats are treated by the Haitesan diterpenoid alkaloid provided by the invention, the quality reduction trend is obviously relieved, and the foot swelling degree and the arthritis score are obviously reduced; bone loss induced by AIA can be effectively inhibited, and the structural integrity of bone trabecula is protected; cartilage matrix degradation can be inhibited, and cartilage erosion damage is relieved; the anti-inflammatory effect can be achieved by inhibiting the expression of key proinflammatory factors in bone tissues.

The invention provides diterpenoid alkaloid in delphinium delphinium as well as a preparation method, application and a pharmaceutical composition of the diterpenoid alkaloid. After rats are treated by diterpenoid alkaloid in delphinium delphinium provided by the invention, the quality reduction trend is obviously relieved, and the foot swelling degree and the arthritis score are obviously reduced; bone loss induced by AIA can be effectively inhibited, and the structural integrity of bone trabecula is protected; cartilage matrix degradation can be inhibited, and cartilage erosion damage is relieved; the anti-inflammatory effect can be achieved by inhibiting the expression of key proinflammatory factors in bone tissues.

The invention provides a composition for improving bone joints and promoting bone health as well as a preparation method and application thereof, and relates to the technical field of compositions. The composition is prepared from N-acetylglucosamine and a turmeric extract. The composition can improve the differentiation activity of cartilage precursor cells, effectively promote synthesis of cartilage matrixes, increase the structural construction ability of cartilage tissues, reverse expression down-regulation of cartilage synthesis markers, down-regulate abnormally high expression of cartilage decomposition markers and maintain metabolic balance of cartilage synthesis and decomposition, and has the effects of improving the cartilage tissue differentiation activity and improving the cartilage tissue differentiation activity. Abnormal high secretion of tumor necrosis factors alpha and interleukin 6 in LPS-induced cartilage cells is reduced, and the effects of resisting inflammation, resisting cartilage degradation and maintaining cartilage metabolism balance are achieved.

The invention provides C20 type diterpenoid alkaloid, a preparation method and application thereof and a pharmaceutical composition. After rats are treated by the C20 type diterpenoid alkaloid provided by the invention, the quality reduction trend is obviously relieved, and the foot swelling degree and the arthritis score are obviously reduced; bone loss induced by AIA can be effectively inhibited, and the structural integrity of bone trabecula is protected; cartilage matrix degradation can be inhibited, and cartilage erosion damage is relieved; the anti-inflammatory effect can be achieved by inhibiting the expression of key proinflammatory factors in bone tissues.