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Bone Tissue Engineering
Bone tissue engineering aims to address the limitations of traditional bone grafting methods through the development of biocompatible substitutes and advanced technologies. It explores various approaches, including the use of synthetic materials and personalized grafts derived from patients' own cells, to enhance bone regeneration and healing. Recent advancements include FDA-approved products and ongoing clinical trials that show promising outcomes for bone repair applications, including 3D-printed grafts.
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Bone Tissue Engineering
- 1. Bone Tissue Engineering ZohaibHussain Tissue Engineering Professor Dr Giyoong Tae School of Materials science and Engineering Gwangju Institute of Science and Technology
- 2. • Introduction • Anatomyand Physiology of bone • Bone Tissue Engineering • Recent studies related to bone tissue engineering • Commercialized products and ongoing clinical trials • Biomedical start-ups • Concluding remarks Contents
- 3. Introduction and Motivation Theglobal market for bone grafts and substitutes now exceeds US$2.5 billion, including over US$500 million for dental and craniofacial applications
- 4. Autologous bone grafts- The "gold standard" - a procedure where bone is relocated from one organ to another in the patient's body. Autologous bone grafting currently accounts for about 40% of all bone reconstruction procedures. Limitations: - An invasive surgical procedure - Donor site morbidity - Insufficient graft volume - Poor graft quality Allogeneic/xenogenic bone grafts - These grafts are obtained from human cadavers, living donors or animal sources. DBM (Demineralized Bone Matrix) is employed which is produced by partial dissolution of bone tissue and consequent gain of vital organic ingredients that support bone cells. Limitations: - Suitable for small bone defects - Inferior bone properties - Risk of infection - Long recovery The ideal bone graft substitute must demonstrate biocompatibility, functional and structural similarity to the defective or deficient bone, ease of use and cost-effectiveness. Treatments
- 9. Short, irregular, andflat bones all consist of thin plates of spongy bone covered by compact bone. There is no well- defined cavity for the marrow to sit in, and hyaline cartilage covers portions of the surface that are involved with joints. Compact bone, which is very dense and smooth. Inside there is lots of spongy bone, which is like a honeycomb of little needles. Typically the open spaces will be filled with bone marrow. The precise arrangement of compact and spongy bone depends on the bone type.
- 11. Periosteum - thefibrous membrane cover the outer surface of the bone. It has blood vessels, nerves, lymphatic vessels that nourish the compact bone. - covers the entire outer surface of the bone, outer surface of the bone except at the epiphysis region where it has articular cartilage. this acts as the shock absorber and reduces the friction. Endosteum-place for bone growth, repair and remodeling
- 12. Flat bones: Craniumit is made up of a layer of a spongy bone and lined on either side of the layer of the compact bones. So, the layer of spongy bone and the two layers of the compact bone works together to protect the internal organs. If there is any fracture in the outer cranial bone still the brain is protected by the inner contact layer of the compact bones. Three general classes of bone markings: (1) articulations, (2) projections, and (3) holes
- 13. Question: Both osteocyteand osteoblast lack mitosis, then there rise the question, if both the cells lack mitosis how are they replenished when old one dies? Answer: Osteogenic cell. It is the only bone cell that can divide, it divide and differentiate into osteoblast cells.
- 14. Osteon is madeof a series of lamellae, which are hollow tubes, Within each lamella are collagen fibers running in a specific direction, with crystals of bone salts in between. This alternating pattern is what gives compact bone the ability to withstand torsion or twisting force Spongy bone is not made up of concentric rings whereas it is made up of lattice like network of matrix spikes called trabeculae. This provides strength to the bone, the spaces in some spongy bones which that contains red marrow which are protected by the trabeculae where haematopoiesis occurs.
- 15. The spongy boneand medullary cavity receive nourishment from arteries that pass through the compact bone. Enter through the nutrient foramen which is the small opening that present in the diaphysis. The osteocytes present in the spongy bone get nourished by the blood vessels and the arteries that enter through the periosteum and into the marrow cavities. Nerves tend to concentrate in the more metabolically active regions of the bone. Nerves also sense pain; the nerves also plays a very important role in regulating blood supplies and bone growth. Blood and nerve supply
- 16. Two Pathways Intramembranous pathwayand endochondral pathway In first intramembranous bone where mesenchymal stem cells are directly developed into osteoblast cells and subsequent bone formation occurs. In endochondral bone endochondral the mesenchymal progenitor cells developed into chondrocytes, first they are developed into chondrocytes. Then they form a cartilaginous layer, cartilaginous matrix, calcified matrix, then they subsequent bone formation occurs. Bone development “modeling” Aghajanian, P., Mohan, S. The art of building bone: emerging role of chondrocyte-to-osteoblast transdifferentiation in endochondral ossification. Bone Res 6, 19 (2018).
- 17. Pathophysiology of boneremodeling
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- 20. Bone defect repair-naturalprocess
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- 22. Timeline of majormilestones in biomaterials design for bone-tissue engineering Koons, G.L., Diba, M. & Mikos, A.G. Materials design for bone-tissue engineering. Nat Rev Mater 5, 584–603 (2020). https://doi.org/10.1038/s41578- 020-0204-2
- 23. Tissue Engineering Strategies (Ovsianikovet al., 2018) 23
- 24.
- 25. Pathway of materialsdesign for bone- tissue engineering Koons, G.L., Diba, M. & Mikos, A.G. Materials design for bone-tissue engineering. Nat Rev Mater 5, 584–603 (2020). https://doi.org/10.1038/s415 78-020-0204-2
- 26. Biomaterial base approach Idealproperties of scaffolds (O'brien, 2011)
- 27. Common material typesfor bone- tissue engineering Biosynthetic substitutes - synthetic or natural biomaterials that promote bone regeneration. Limitations: - Inferior bone properties - Suitable for small bone defects - Long recovery
- 28.
- 29. Limitations: - Inferior boneproperties - Suitable for small bone defects - Long recovery Growth factor base approach
- 30. Ideal scenario forbone tissue engineering
- 31. PCL and PCLcomposites (PCL–HA, PCL/TCP, etc.) obtained by Fused Deposition Modelling (FDM) These so-called first- generation scaffolds have been studied for more than 5 years in a clinical setting, have been commercialized (http://www.osteoporeinternational.com) and have gained Federal Drug Administration (FDA) approval. Schantz et al. (2006) used FDM-fabricated PCL scaffolds as burr hole plugs in a pilot study for cranioplasty. The clinical outcome after 12 months was positive, with all patients tolerating the implants, no adverse side-effects reported and good cosmetic and functionally stable cranioplasty observed in all cases. Same group studied mPCL–CaP composite scaffolds for cranial, osteochondral and spinal fusion in animal models 1st and 2nd Generation scaffolds for bone tissue engineering
- 32. Liu, M., Zeng,X., Ma, C. et al. Injectable hydrogels for cartilage and bone tissue engineering. Bone Res 5, 17014 Injectable hydrogels for bone tissue-engineering applications
- 33. Macrophage-derived small extracellularvesicles promote biomimetic mineralized collagen-mediated endogenous bone regeneration Liu, A., Jin, S., Fu, C. et al. Macrophage-derived small extracellular vesicles promote biomimetic mineralized collagen- mediated endogenous bone regeneration. Int J Oral Sci 12, 33 (2020)
- 34. https://doi.org/10.1021/acsami.0c00275 Intrafibrillar Mineralized Collagen–Hydroxyapatite-BasedScaffolds for Bone Regeneration ACS Appl. Mater. Interfaces 2020, 12, 16, 18235–18249
- 35. Highly osteogenic MSCline generated from induced pluripotent stem cells that generates high yields of an osteogenic cell-matrix (ihOCM) in vitro. The intrinsic osteogenic activity of ihOCM surpasses bone morphogenic protein 2 (BMP2) driving healing of calvarial defects in 4 weeks by a mechanism mediated in part by collagen VI and XII. We propose that ihOCM may represent an effective replacement for autograft and BMP products used commonly in bone tissue engineering. b High-power micrographs of healed specimens indicating trabecular micro-structure of newly formed bone (bar = 75 μm). Yellow boxes in panel a indicate the enlarged region in panel b. c Healing index of defects. McNeill, E.P., Zeitouni, S., Pan, S. et al. Characterization of a pluripotent stem cell- derived matrix with powerful osteoregenerative capabilities. Nat Commun 11, 3025 (2020). https://doi.org/10.1038/s41467-020-16646-2 Characterization of a pluripotent stem cell-derived matrix with powerful osteoregenerative capabilities
- 36. Graphic representation ofthe ultrasound-mediated gene therapy for segmental bone repair. (1) Non-union bone fracture. (2) Collagen sponge insertion. (3) Stem cell migration into the sponge (4) Injection of microbubbles and therapeutic gene. (5) Sonoporation/Ultrasound application. Bone grafting can be complicated, as bone cells are not always available and their harvest, usually from the pelvic bone, can lead to prolonged pain. The Gazit Laboratory is developing a novel approach for the treatment of bone fractures without the need for bone grafting. Targeting of Endogenous Stem Cells for Segmental Bone Fracture Repair Sci Transl Med. 2017 May 17; 9(390):pii:eaal3128.
- 38. Commercial product (name) Substitute materialsProperties Applications Osteograf Ceramic Osteoconductive, limited osteoinductive when mixed with bone marrow Bone void filler NovaBone Bioactive glass Osteoconductive, limited osteoinductive when mixed with bone marrow Filling surgical or traumatic bone gaps Osteosat Surgical grade calcium phosphate Osteoconductive and bioresorbable Hip and knee joint repair Calceon 6 Calcium sulfate Osteoconductive and bioresorbable Bone void filler; provides strength Norian Monocalcium phosphate, tricalcium phosphate, and calcium carbonate Good compressive strength Skull bone defect; injectable paste, craniofacial reconstructions Hard tissue-replacement (HTR) Poly methyl methacrylate (PMMA) Good strength, durable, and surface osteoconductive Craniofacial reconstruction Alpha BSM Calcium phosphate cement Good compressive strength Dental application for bone and cartilage defects Mimix Synthetic hydroxyapatite tetra-tricalcium phosphate Good compressive strength Cranial defects ELIZ (Kyeron) Composed of (40%) β-tricalcium phosphate and of (60%) hydroxyapatite Ultrahigh porosity, biocompatible, and osteoconductive It has been successfully implanted in more than 1200 patients without any side-effects. OSIQ (Kyeron) Fully synthetic ultrapure nano-hydroxyapatite Ready to use, injectable, and biodegradable Filling or reconstruction of small and medium bone defects AXOZ QS (Kyeron) Resorbable phosphocalcic compounds and a polymer Injectable and fully resorbs Supports bone growth COLLAPAT II (Symatese) Composed of a collagen structure in which ceramised hydroxyapatite granules are dispersed Strong hemostatic power, completely resorbable in a few weeks, and osteoconductive Induces bone substance replacement in maxillofacial surgery and odontostomatology CopiOs (Zimmer Biomet) Bone Void Filler Calcium phosphate, dibasic (DICAL), and highly purified Type I bovine collagen DICAL provides significantly more calcium and phosphate ions at equilibrium than either β-TCP or HA CopiOs paste acts as an osteoconductive scaffold for the growth of new bone List of some commercially available synthetic materials and their applications. Dahiya, U. R., Mishra, S., & Bano, S. (2019). Application of Bone Substitutes and Its Future Prospective in Regenerative Medicine. In Biomaterial- supported Tissue Reconstruction or Regeneration. IntechOpen.
- 39. Commercial product (name) Substitute materialProperties Applications Cortoss Polymer system with reinforcing particle bioactive glass Forms biological interface Augmentation of screws in osteoporotic bone (hip, spine, etc.) Open porosity polylactic acid polymer (OPLA) Polylactic acid Osteoconductive and bioresorbable Articular cartilage regeneration Collagraft Mixture of tricalcium phosphate, bovine collagen, and hydroxyapatite Bioresorbable and osteoconductive Use for the treatment of long bone fracture and void filling DynaGraft Demineralized bone matrix Heat sensitive copolymer, injectable gel, limited osteo-induction Dental bone graft substitute MedPor Porous polyethylene Higher porosity Orbital reconstruction and facial contouring Collapro/matrix Human collagen in lyophilized strip Lack of immunogenic property Use in development Healos Hyaluronic acid-coated collagen sponge Osseo-inductive property Replacement of autograft/autograft extender for spinal fusion Immix PGA/PLA polymer to be produced in chip, flex forms Provides structural support Bone graft extender OsteoScaf (Bonetec) Macroporous poly(lactide-co- glycolide)/calcium phosphate (PLGA/ CaP) foam matrices Fully resorbable, osteoconductive, and mechanically robust Heal tissue defects List of some commercially available polymer-based graft materials and their applications. Dahiya, U. R., Mishra, S., & Bano, S. (2019). Application of Bone Substitutes and Its Future Prospective in Regenerative Medicine. In Biomaterial- supported Tissue Reconstruction or Regeneration. IntechOpen.
- 40. A Tailor-made bonegraft: Personalized bone regeneration by using culture expanded autologous cells and biomaterials The cells autlogous (self) origin eliminates the risk of tissue rejection and surgery failure. The adipose tissue required for the production of adipose-derived cells is harvested in a simple and minimally invasive procedure. The scaffold's unique nano-structure optimally supports cell expansion in vitro (in the laboratory) and provides the desired supporting properties in vivo (in the patient). Personalized, available-on-demand product aimed to treat a variety of bone and joint conditions. It is individually designed to precisely fit the anatomical shape of the bone void in question. Growing trend and advanced approach
- 41. Injectable bone graft: Providedin a pre-filled syringe containing bone- inducible cell-seeded matrix particles. This product is suitablee for well-defined bone repair applications such as jaw bone cysts Anatomically pre-designed bone graft: The scaffold is cut to precisely match the patient's 3D Computed Tomography (CT) image. This product aims to repair large/ segmental bone defects. BonoFillTM is currently being performed in phase I/II clinical study, for maxillofacial bone augmentation and regeneration. https://www.bonusbiogroup.com/index.php/products/bonofill
- 42. Personalized maxillary boneregeneration by using culture expanded autologous bone marrow stem cells and biomaterials https://www.maxibone.eu/page-d-exemple/about-maxibone/ Sarted in January 2018 as a four year program with an European funding of 6 million euros. The consortium gathers 12 partners from 6 European countries including research laboratories, academic hospitals, cell therapy units, an SME manufacturing biomaterials and the global leader of dental implants. The FP7-Reborne project, a phase 2 clinical trial, received European funding from 2010 to 2015. The H2020-Maxibone project, a phase 3 clinical trial, has received two European grants and is scheduled to start in early 2019.
- 43. Next 21 K.K.to commercialize CT Bone, 3D printed bone grafts, in Japan, Europe and other Asian countries • 3D Printed Bone Grafts – Japan-based Next 21 K.K. received formal approval from Ministry of Health, Labor and Welfare (MHLW) to 3D print synthetic bone grafts made of calcium phosphate, called CT Bone, for patients •Accurate and Compatible – 3D printing allows bone grafts to be made with 0.1 millimeter accuracy, with curing method applied so material can assimilate with patient’s existing bone quickly •Study Results – 3D printed implants were placed on 23 sites for 20 patients with facial bone deformities and results show sufficient bone union in 19 sites with no serious defects and no change observed in shape of CT bones •Commercialization – Company to commercialize technology in Japan and other Asian countries, and will work with Dutch company Xilloc on licensing to expand manufacturing and sales in Europe CT-Bone® CT-Bone® is not yet available. CT-Bone® is a 3D printed calcium phosphate that unifies with the patient’s bone. It can be used for bony augmentations (non-load-bearing) and is converted into real bone in the patient. Because it is 3D printed it can be made into complex shapes with controlled porosity. Autoclave (steam) sterilisation. Histological investigations showed that in the hydroxyapatite, bone-like tissue was only found in some micropores close to the surface. In CT-Bone®, large bone-like tissues penetrated into the macropores, containing activated osteoclasts, fibroblasts and even blood vessels. In addition, bone marrow formation was observed containing erythroblasts and megakaryocytes.
- 44. Grow bones fromyour own cells: EpiBone is developing technology to create bone tissue from a patient's mesenchymal stem cells in vitro for use in bone grafts. https://www.epibone.com/technology/
- 45. The ideal bonegraft substitute must demonstrate biocompatibility, functional and structural similarity to the defective or deficient bone, ease of use and cost-effectiveness. Bone tissue engineering has been developed as a promising alternative to bone grafting and as a solution exhibiting the three required processes of bone healing: osteogenesis, osteoinduction and osteoconduction. Current limitations: Identification of the ideal cell population for transplantation Inefficient procedures for cell isolation Expansion on the scaffold Preparation for grafting Lack of sufficient and timely vascularizations To address the limitations of existing bone regeneration therapies, multidisciplinary team of scientists, engineers, clinicians need to work together to design strategy that precisely fit the patients needs and feature all ideal bone graft characteristics. Concluding Remarks
- 46. Thank you somuch; If you have any question please ask
Editor's Notes
- #6 Bones can be placed into two categories, axial and appendicular. Axial bones are found in the head and torso, making up the spine, rib cage, and skull. Appendicular bones make up our appendages, or limbs, those being the arms and legs, as well as the pelvis and shoulders.
- #7 Bones can also be classified by shape, being either long, short, flat, or irregular. Long bones are longer than they are wide, like the ones in our limbs. Short bones are cubelike, found in the ankles and wrists among other places. Flat bones are thin and often curved, like the sternum and shoulderblades. And irregular bones are the ones that have complicated shapes that don’t fit into the other three categories, like vertebrae and hip bones.
- #8 Bones protect organs Bones support body Bones act as lever Mineral storage ca and p enter into blood stream when required Fat sotrgae Harmone production Blood cell formation
- #9 Schematic illustration of a distinct hierarchical structure of bone tissue. (a)At the macrostructural level, bone is composed of cortical bone and cancellous bone. (b) At the microstructural level, the cortical bone is made up of repeated units of osteon, which is characterized by 20–30 concentric layers of collagen fibers, called lamellae. The lamellae surround the central canal and contain various blood vessels and nerves. (c) At the nanostructural level, there are large numbers of collagen fibers, which are composed of periodic collagen fibrils and gaps between the collagen molecules. The calcium phosphate crystals and non-collagenous organic proteins are embedded in these gaps between collagen molecules.76
- #10 We will have to examine bones at a few levels of complexity, starting with gross anatomy, meaning the part that is visible to the naked eye. The outer layer of any bone is made of
- #11 Long bones are a little different. These contain a tubular shaft, called a diaphysis. This is made of a thick collar of compact bone surrounding a medullary cavity, or marrow cavity. In adults, this cavity contains yellow bone marrow which is high in fat. The ends of a long bone are called epiphyses. These parts do contain spongy bone inside the compact bone, and again, cartilage covers the joint surface for cushion and stress absorption. Beyond the yellow marrow we mentioned, there is also red marrow, which can be found inside the cavities of spongy bone, and this type of marrow produces blood cells.
- #12 We can also see an epiphyseal line, which is a remnant of the epiphyseal plate, a disc of cartilage that grows during childhood, which is how these bones get longer as a child gets taller. A white membrane called the periosteum covers the exterior of the bone, consisting of an outer fibrous layer made of dense irregular connective tissue, and an inner osteogenic layer, containing primitive stem cells. This membrane is attached to a network of nerve fibers and blood vessels, which then pass through the shaft to the marrow cavity, and perforating fibers connect the periosteum to the bone. Endosteum covers the internal spongy bone layer, as well as canals that pass through the compact bone. Now that we have this view covered, let’s zoom in a little more and check out the microscopic anatomy of a bone. We can find a few different types of cells in here, so let’s go through each one. First, osteogenic cells. These are a type of stem cell that actively divide, and they are found in the periosteum and endosteum that we mentioned. If the bone is growing, these are flattened or squamous cells, and they can differentiate into other types at certain times. Next are osteoblasts. These are the ones that secrete the bone matrix that consists of collagen and other proteins, meaning they are responsible for bone growth. These are also actively mitotic, and cube-shaped while active. Once surrounded by matrix, they become our next type of cell, osteocytes. These are mature bone cells that monitor and maintain the bone matrix, communicating this information to other cells. Next are bone lining cells, which are flat cells found on the surface of the bone. These also help maintain the matrix. And lastly, osteoclasts. These are large cells with multiple nuclei that use enzymes to break down bone, which is a normal process called resorption that releases minerals to be transferred to the blood.
- #13 an articulation is where two bone surfaces come together (articulus = “joint”). These surfaces tend to conform to one another, such as one being rounded and the other cupped, to facilitate the function of the articulation. A projection is an area of a bone that projects above the surface of the bone. These are the attachment points for tendons and ligaments. In general, their size and shape is an indication of the forces exerted through the attachment to the bone. A hole is an opening or groove in the bone that allows blood vessels and nerves to enter the bone. As with the other markings, their size and shape reflect the size of the vessels and nerves that penetrate the bone at these points.
- #14 Osteoblasts cells are the bones cells responsible for the formation of bone. It is present in the growing structures and it is called osteocyte and which is the primary cell for the mature bone. And, the places where the osteocytes located are called as lacunae. Osteocytes maintain the mineral concentration within the matrix. Osteoblast and osteocytes communicate with each other and exchange their nutrients through the long cytoplasmic processes via canaliculi which is canaliculus which is present inside the bone matrix. Both osteocyte and osteoblast lack mitosis, then there rise the question, if both the cells lack mitosis how are they replenished when old one dies? The answer lies in the third category, third property of cell which is osteogenic cell. It is highly undifferentiated cell and it is present in the deep marrow present in the deeper regions of periosteum and marrow cavities. It is the only bone cell that can divide, it divide and differentiate into osteoblast cells. So, while explaining the function of bone the last function where I said bonus is dynamic in nature, which means the new bone is constantly formed and the old bone that or the damaged bone or the repaired bone should be resorbed continuously, which was, which is done by the cells called osteoclast cells. Osteoclast cells are responsible for bone resorption. So, there should be a constant balance between osteoblast cells which are responsible for the formation of new bone and osteoclast cells which are responsible for the bone resorption in order to maintain the structural integrity of the bone. So, this reviews the cell type, its function and location in the bone. First cell type is osteogenic cells, as I said it is the only cell that can divide and it develop into osteoblast. It is present in the deep layers of periosteum and the marrow. And, the next is osteoblasts cells which are responsible for the formation of bone and present in the growing portions of bone including periosteum and endosteum. Osteocytes which are the primary cell for a matured bone and the location where it is located it is known as lacunae. And, it maintains the mineral concentration of matrix which are entrapped in matrix. Osteoclasts cells are responsible for bone resorption and it is present at the bone surfaces and at sites of old injured or unneeded bone. These osteoclasts cells are formed from monocytes or macrophages which are two white blood cells, they are not originated from osteogenic cells.
- #15 First let’s check out the compact bone in the shaft. This is actually not solid all the way through, there are many cylindrical units with open canals at the center, and each of these units is called an osteon. If we were to pull one of these out of the bone, we would see that it is made of a series of lamellae, which are hollow tubes, and these are arranged like the rings of a tree trunk. Within each lamella are collagen fibers running in a specific direction, with crystals of bone salts in between, and as we proceed inward, the next lamella will have its fibers running in another direction, continuing in this fashion all the way to the center. This alternating pattern is what gives compact bone the ability to withstand torsion, or twisting force. The open region at the center is called the central canal, and it contains blood vessels and nerve fibers that serve the cells in that osteon. There are also shorter canals running perpendicular, allowing for connections to run all the way from the periosteum to the central canals to the medullary cavity. Where the lamellae meet we can find tiny gaps called lacunae, and these are filled with osteocytes. The lacunae are connected by extra-tiny canals called canaliculi. Beyond the lamellae found within osteons, there are others called interstitial lamellae, that fill in gaps between osteons, as well as circumferential lamellae, which make up the circumference of the diaphysis, surrounding all the osteons.
- #17 a Endochondral ossification. Mesenchymal stromal cells develop into two different lineages, chondrogenic and osteogenic with no other intermediates. b Intramembranous ossification. Osteoblast development does not require the formation of a chondrocyte template. Mesenchymal stromal cells directly differentiate in an osteogenic lineage. c Chondrocyte to osteogenic precursor. Immature chondrocytes differentiate into an osteogenic precursor population which then differentiate into pre-osteoblasts and osteoblasts. d Dedifferentiation to redifferentiation. Hypertrophic chondrocytes dedifferentiate into immature chondrocytes, which directly differentiate to an osteogenic fate. e Direct transdifferentiation. Hypertrophic chondrocytes directly differentiate to osteoblasts.
- #18 Then the remodelling of bone takes place, we know that the skeleton is a metabolically active organ that undergoes continuous remodelling throughout the life. This remodelling is necessary in order to maintain the structural integrity as well as to maintain the mineral concentration within the matrix. Remodelling of bone begins at the early fetal stage and also once the skeleton is fully formed in young adults, afterwards all the metabolic activity will takes place in this form.
- #19 This remodelling consists of highly regulated series of; this consists of series of highly regulated steps which involves the interaction of two cell lineages, two cell lineages. They are mesenchymal osteoblastic cells and hematopoietic osteoclastic cells. The interaction between mesenchymal osteoblastic cells and hematopoietic osteoclastic cells precursors cells leads the it the start of the remodeling phase. And, there are four phases in remodelling of a bone: activation phase, resorption phase, reversal phase and formation of the phase. The first phase is the activation phase where the interaction between the two precursors cell lines happens. So, which results in the formation, differentiation, fusion of and formation of the large osteoclasts cells. Osteoclast cells which are present at the surface of the bone matrix, these cells will tend to secrete hydrogen ions, hydrogen ions as well as the lysosomal enzymes. Especially cathepsin C, cathepsin K; cathepsin K these two will degrade all bone cellular components including collagen at low pH. And, this is the resorption phase, the resorption phase where the cells interact with the hematopoietic precursors to form osteoclasts and the reversal phase the complete resorption takes place. The complete resorption of bone by osteoclasts takes place in the reversal phase and initiates the formation phase. In this formation phase, mesenchymal osteoblastic cells will form, will start to produce osteoblasts, which which fills the cavity which are resorbed by the osteoclasts thereby it laid down the bone matrix. So, this how the remodelling of bone occurs; the first is the interaction of between two precursors cell lines which is hematopoietic osteoclasts cell and mesenchymal osteoblasts. And then they form the osteoclasts cells. This osteoclast cell involve in bone resorption and it resorbs the bone matrix completely whereas, there is an formation of osteoblast cells which fills the cavity of the bone resorbed matrix. So, this is how bone modelling and remodelling, formation of bone occurs.
- #20 If there are any abnormalities present in this bone remodelling will lead to various skeletal disorders. For example, osteoporosis, hypothyroidism and hyperthyroidism, hyperparathyroidism and hyperthyroidism, Paget disease, orthopaedic disorders, osteopetrosis. These are the skeleton disorders which are due to abnormalities happen in the bone remodelling cycle. So, osteoporosis - osteoporosis is defined as the loss of bone mass and strength which leads to the increase in propensity to fracture. It is type 1 and type 2; type 1 is called as postmenopausal osteoporosis and type 2 is called as senile osteoporosis. Recently studies have, literature have proved that deficiency of oestrogen which is the important systemic hormone for the bone turnover; if there is deficiency of oestrogen it leads to osteoporosis. So, this deficiency or the osteoporosis reasons can be mainly due to three reasons; one the peak, peak bone mass is not formed completely or there is a imbalance between osteoclast function and osteoblast function or the over activeness of osteoclast. Like over osteoclasts are activated too much thereby it resorbs bone more than the bone formation, that is osteoporosis. And, Paget disease again they complete mechanism or the clear mechanism is not yet understood. But, they say that the because of some viral infection this osteoclast cells are activated abnormally and thereby bone resorption is more, where it changes the structural structure of the bone, where it shows in the evident in that picture that is Paget disease. In osteopetrosis, osteoblasts function is lost, loss of osteoblast function; bone formation is not that great when compared to bone resorption. So, there should be a balance between the formation of bone or the resorption of bone, in order to maintain a proper shape of the bone; otherwise it will lead to a variety of skeletal disorders.
- #21 is any fracture, bone can itself heal by its process. It can be repaired by the process of both intra membranous and endochondral bone formation. It first it starts with the hematoma formation accompanied by the inflammatory response, then it start recruiting the signalling molecules. For example: interleukin, fibroblast growth factors, bone morphogenetic proteins which are responsible for the formation of bone. Once after recruiting signalling molecules at the place of cortex and periosteum intra membranous formation, bone formation immediately occurs. Then it stabilizes the fracture by the formation of callus which is under which with by chondrogenesis. Chondrogenesis is the activation of chondrocytes which is highly similar to endochondral ossification. Then once the tissue reaches its maturity, the chondrocyte proliferation decreases and they calcify the matrix, the growing blood vessel which carries chondroclasts and osteoblastic progenitors. This chondroclasts will resorb the calcified cartilage and whereas, the osteoblastic progenitors will helps in the formation of new bone and the remodelling of new bone will starts; so, thus by it heals the repair or fracture. As we know that bone is highly vascularized tissue, though it can heal by itself beyond certain point or beyond critical point clinical intervention is required; where the future treatment option is bone tissue engineering. Bone tissue engineering is considered to be the future treatment option. In next session we will be discussing about is status or key components involved in the bone tissue engineering. Thank you.
- #23 . Initial efforts towards bone repair involved the use of calcium phosphates and bioresorbable metals, which were followed by observations of bone formation in polymeric materials and the invention of Bioglass, the first human- made material capable of bonding to living tissues. Further work led to the identification of bioactive molecules such as proteins and peptides, after which bone-tissue engineering emerged as a separate research field. Subsequently, scaffolds were designed using different material types and were modified to induce specific biological responses. Throughout the development of biomaterials for use in bone- tissue- engineering applications, regulatory agencies have evaluated products containing various biomaterials and have deemed several commercial products suitable for clinical use. BMP, bone morphogenetic protein; FDA, US Food and Drug Administration; RGD, arginine–glycine–aspartic acid.
- #26 3D, three- dimensional. The materials- design pathway begins with astrategic selection, which is followed by bthe optimization cycle. cFinally, the performance of materials is evaluated, which might direct the materials developer to return to the boptimization cycle
- #30 Paracrine is nothing but where they act on the neighbouring cells, the signal transfer take place in the neighbouring cells. In autocrine as it defines like it acts on itself the same cell. Endocrine where it is transfer in the blood and tissues and it transported through the blood and in the targeted site, it will enhance its property or elucidate its response.
- #32 (A) Two full-thickness critical bone defects (5 mm in diameter) were created in the rat parietal bone. Bone chips are shown after trephination (arrows). (B) Implantation of PCL–TCP–Col1 scaffolds into the defects; inset, PCL–TCP scaffold (5 mm diameter and 1 mm thick, 0–90 ◦ lay-down pattern, 70% porosity) before treatment (left) and after lyophilization of 350 µg rat tail collagen 1 (right). (C, D) Micro-CT scanning of the skull defect showing the bone formation with and without scaffold after 14 months of implantation. It can been seen in (D) that >90% of the original critical size defect is filled with bone. (b) Implantation of a Mesenchymal stem cells (MSC)-loaded mPCL–CaP scaffold into the bone in a high load-bearing osteochondral defect. (c) Implantation of a MSC-loaded mPCL–CaP scaffold in a pig spinal fusion model. The mechanical testing of mPCL-TCP scaffolds show the high reproducibility of the manufacturing process (d) mPCL-TCP scaffolds seeded with BMSC’s were implanted for 2 years in a critical size (15 mm) skulkl defects of New Zealand white rabbits. Analysis of the tissue engineered constructs (TEC) showed bone formation throughout the entire scaffold and no fibrous tissue formation. MicroCT analysis revealed that 30% of the mPCL-TCP is resorbed and replaced by bone
- #35 https://doi.org/10.1021/acsami.0c00275
- #36 Stem cells are usually extracted from the marrow of an adult bone and are, as a result, older. Their age affects the cells' ability to divide and produce more of the precious extracellular matrix. Pluripotent stem cells, unlike adult mesenchymal cells that have a relatively short lifetime, they noted that these primitive cells can keep proliferating, thereby creating an unlimited supply of mesenchymal stem cells needed to make the extracellular matrix for bone grafts- can be made by genetically reprogramming donated adult cells. Induced the pluripotent stem cells to make brand new mesenchymal stem cells, they were able to generate an extracellular matrix that was far more biologically active compared to that generated by mesenchymal cells obtained from adult bone Implanted it at a site of bone defects-pluripotent stem-cell-derived matrix was five to six-fold more effective than the best FDA-approved graft stimulator.
- #37 Stem cells are recruited to the fracture site using a collagen matrix and then a bone-forming gene is directly delivered to the stem cells using an ultrasound pulse his proposed therapy has the potential to generate rapid healing of segmental bone fractures and significantly decrease patient hospitalization, loss of working days and significant healthcare costs. In addition, this therapeutic intervention can be repeated several times when needed in order to deal with severe cases of bone loss.
- #42 Bonus BioGroup developed a unique method to grow three dimensional (3D), high-density, multi-cell bone grafts - BonoFillTM . These grafts are produced from patients' adipose (fat) tissue-derived cells, are designed to precisely fit the patients' deficient anatomical sites, and feature all ideal bone graft characteristics.