MM517 Lecture 4 - Bone PDF

MEC1052 - Advanced Biomechanics & Tissue Engineering Lecture 4: Bone Tissue Bone －How many bones are in the adult human body? －206 －Although varies from person to person – 1 in every 8 people has an extra, thirteenth pair of ribs, while people with Down’s syndrome are frequently...

MEC1052 - Advanced Biomechanics & Tissue Engineering Lecture 4: Bone Tissue Bone －How many bones are in the adult human body? －206 －Although varies from person to person – 1 in every 8 people has an extra, thirteenth pair of ribs, while people with Down’s syndrome are frequently missing a pair. －Doesn’t include sesamoid bones (i.e. present within tendons) e.g. the knee cap  Function of Bone －Provide shape and support for the body －They provide rigid levers for muscles to pull against. －Protect the organs －Produce blood cells －Store and release fat －Store and release minerals －Produces hormones e.g. osteocalcin －Osteocalcin has many functions e.g. managing glucose levels, boosting male fertility, influencing mood, affecting memory －Bones are both light and strong －They are stronger than reinforced concrete yet light enough to allow us to sprint. They weigh no more that 9kg and can withstand a ton of compression.1 1Bill Bryson, The Body – A Guide for Occupants, 2019  2.0 Basic Composition of Bone Bone is a composite material Consists of an organic component (mostly collagen) and mineral component (hydroxyapatite) - The main constituents of bone are collagen (20 wt.%), calcium phosphates (69 wt.%) and water (9 wt. %) - Also contains: proteins, polysaccharides, and lipids. This results in a stiff but tough material  2.0 Basic Structure of Bone Epiphyses Metaphysis Diaphysis Articular cartilage Marrow cavity - Red marrow – Blood cells - Yellow marrow – Fat/bone cells  2.0 Basic Structure of Bone Two types of bone: Cancellous Bone - Spongy & trabecular Cortical Bone - Dense & compact Ratio varies depending on anatomical location  2.0 Cortical Bone Osteon Consists of central canal (Osteonic/Haversian canal) surrounded by concentric rings of matrix (lamellae). Haversian canals contain blood vessels that connect with vessels on the surface of bone. Transport system for nutrients Each canal contains one or two capillaries and nerve fibres  2.0 Cortical Bone (Histology)  2.0 Cortical Bone Interstitial lamellae Packets of bone between osteons Canaliculi Canals connecting lacunae to each another and to haversian canals Lacuna – Hole for osteocyte Osteons Circumferential lamellae Interstitial Tubular arrangement of lamellae Trabeculae lamellae gives bone greater strength than solid structure of same size. Lamellae Canaliculi Cancellous Bone Highly porous bone - Represents 20% of skeletal mass - But 80% of bone surface Less dense, more elastic and higher turnover rate than cortical Consists of microscopic framework of plates and rods (trabeculae) Large pores contain marrow and cells Canaliculi receive blood supply from bone marrow Found in epiphyseal and metaphyseal regions of long bones and throughout interior of short bones Cancellous Bone Highly resistant to compressive loads Analysis of stress Trabeculae organised to provide patterns in maximum strength crane - Aligned along lines of stress trajectories Trabeculae Trabecular - Few lamellae and cells alignment: femur - Cell blood supply by canaliculi  2.0 Rate of Formation Woven Bone (Fast) Irregular collagen fibres Many Osteocytes Foetal bones/Fractures Lamellar Bone (Slow) Regular collagen fibres Few osteocytes Collagen Structural Protein Type 1 – gives bone flexibility and strength Formed as chains (short pieces of thread) Which twist into triple helices (strings) Collagen triple helices form spontaneously from nanoscale bundles of protein Fibrils are arranged in layers, mineral crystals deposit between layers  2.0 Mineral Essential for hardness and rigidity that enable skeleton to resist loading Main component of bone is hydroxyapatite Comprises ~50% bone volume and 75% dry bone mass Mineral crystals are deposited along bone collagen fibrils of the osteoid (newly formed bone) soon after its deposition  2.0 Bone Cells Osteoprogenitor cells differentiate into osteoblasts Osteoblasts synthesize new matrix – Osteogenesis Osteocytes = mature bone cells – In lacunae – Connected by canaliculi Osteoclasts dissolve bone matrix – Osteolysis 16 Bone Cells Osteocytes Most abundant cell type - 95% of bone cells Reside within evenly distributed lacunae Cell processes connect Osteocyte enabling communication lacuna Osteocyte between osteocytes and bone lining cells Channels (canaliculi) radiate from lacunae to osteonic (haversian) canals to provide Cell Process nutrients Osteocytes Secrete growth factors to activate lining cells or stimulate osteoblasts and osteoclasts Exact role is unclear - likely to direct bone remodelling to accommodate mechanical strain and repair fatigue damage Osteoblasts Make proteins that form bone matrix and control mineralization. After bone formation: - Become entrapped in matrix and differentiate into osteocytes. - Others remain on new bone and differentiate into lining cells - Others undergo apoptosis Osteoclasts Large multinucleated cells Mature osteoclasts are formed from fusion of precursors - Receptors on the osteoclast precursors are activated by factors secreted by osteoblasts and osteocytes Osteoclasts resorb bone After resorbing bone, they undergo apoptosis  2.0 Bone Formation Endochondral ossification: During embryonic development of long bones, cartilaginous tissue develops into bone Chondrocyte proliferation Chondrocyte hypertrophy (swelling by accumulation of water) Mineralization Bone Formation Bone Formation Intramembranous ossification Osteoprogenitor cells differentiate into osteoblasts Osteoblasts lay down matrix (osteoid) Mineralization  2.0 Bone Modelling After ossification, bone differentiation continues within the tissue. - Osteoclasts and osteoblasts build the characteristic microstructure of bone. - This is called modelling. Activation – Formation Activation – Resorption Bone Remodelling After tissue has matured, osteoclast resorption and osteoblast formation continually maintain bone. This is called remodelling. Removes micro-cracks and damage Remodelling is carried out by the Basic multicellular units (BMUs): collaboration of osteoclasts and osteoblasts. Bone Remodelling  2.0 Bone Remodelling In cortical bone, BMU forms a cylindrical canal, burrowing at a speed of 20-40μm/day. Cutting cone: ~10 osteoclasts dig a circular tunnel Closing cone: thousands of osteoblasts that fill the tunnel to produce an osteon of renewed bone. Bone Remodelling In cancellous bone, same sequence of cellular events but bone is laid in pancake-like packets. Most metabolic bone diseases occur from perturbations in remodelling BMU dynamics  2.0 Bone Remodelling Osteoporosis is a debilitating bone disease - occurs through imbalance in remodelling process 1 in 2 women and 1 in 4 men over 50 will have osteoporosis-related fracture in their lifetime More women die from osteoporosis than breast, ovarian, and uterine cancers combined  2.0 Bone Formation Not just a matter of more bone, it’s a better design  13 Wolff’s Law Bone remodelling “Bone adapts its internal shape and external conformation in response to the mechanical loads acting on it”, Wolff’s Law (1892) Bone adaptation during skeletal growth and development continuously adjusts skeletal mass and architecture to changing mechanical environments. Modelling in bone internal architecture The bone in a professional tennis players serving arm may be 30% thicker than in their other arm. Adaptation around prostheses Adaptation/degeneration over life (osteoporosis) Wolff’s Law Physiological paradigm for Wolff's law Bone has "mechano-receptors" or "sensors" distributed throughout the tissue. The mechano-receptors sense the biomechanical signal and emit a chemical (or electrical) stimulus which generates a new activity pattern for the osteoclasts (bone resorbing cells) and osteoblasts (bone forming cells). As the bone changes shape in response to the new forces, the stimulus emitted by the mechanoreceptors reduces until the bone assumes a suitable shape － to carry the new load. Wolff’s Law There are two possible mechanisms relating sensor activation to mechanical loads: (i) Deformations of the lacunae under load. This causes fluid flow in the lacunae which stimulates the osteocytes. (ii) Microdamage in the form of inter-constituent microcracks. Microcracks stimulate the sensors, either by altering the local tissue deformation, or by changing the biochemical environment in the tissue by release of growth factors. －Both of these  2.0 Wolff’s Law & Optimum Design Trabecular trajectories roughly align with the direction of max principal stress Three rules that govern bone adaptation - The Dynamic Stimulus - A case of diminishing returns - Bone cells accommodate to routine loading 1Turnet et al. (1998) Three Rules for bone adaptation to mechanical stimuli, Bone 23,5, 399-407  2.0 Rule 1 - The Dynamic Stimulus Dynamic strains, rather than static strains, are the primary stimulus of bone adaptation Rubin and Lanyon1 demonstrated, using the isolated avian ulna model, that newly formed bone area is proportional to applied strain magnitude. 1C.T. Rubin, L.E. Lanyon, Regulation of bone mass by mechanical strain magnitude Calcif Tissue Int, 37 (1985), pp. 411-417  2.0 Rule 1 - The Dynamic Stimulus Loading frequency (high frequencies e.g. 10Hz) - No effect if applied at < 0.5Hz - No greater effect if > 10Hz 𝐸 = 𝑘1 𝜀𝑓 𝐸 = 𝑘1 ෍ 𝜀𝑖 𝑓𝑖 where, E = strain stimulus k1 = proportionality constant ɛ = peak to peak strain F = frequency rBFR/BS - Relative bone formation rate  2.0 Rule 2 - A case of diminishing returns Extending duration of loading does not yield proportional increases in bone mass - Cells become desensitised - Bone tissue sensitivity is proportional to 1/(N+1) 𝐵𝑜𝑛𝑒 𝐹𝑜𝑟𝑚𝑎𝑡𝑖𝑜𝑛 = 𝑘2 log(𝑁 + 1) where, E = strain stimulus k2 = proportionality constant N = Number of cycles  2.0 Rule 2 - A case of diminishing returns Bone cells will resensitise to loading if they are given a period of rest −𝑡ൗ 𝑅𝑒𝑐𝑜𝑣𝑒𝑟𝑦(%) = 100(1 − 𝑒 𝜏) where, t = time between bouts τ = time constant approx equal to 6hrs  2.0 Rule 3 - Bone cells accommodate to routine loading Bone cells have memory of previous mechanical environment - Threshold over which a response is elicited (neutral axis in bone bending) - Cytoskeletal reorganisation - Extracellular microenvironment reorganisation (osteocytes alter lacunae) Greatest influence on bone formation is the initial loading stimulus  2.0 Disuse and Bone Loss Disuse of bone results in low stress - Decreased bone formation and increased bone turnover/resorption - E.g. Bedridden, Cast, Astronaut. Why do we need tissue engineered bone grafts? Bones are one of the most regenerative tissues, but larger defects are difficult to heal naturally. Chronic Conditions and Osteoporosis: People with conditions like osteoporosis, osteogenesis imperfecta, or other bone-degenerative diseases often suffer from poor bone healing. Need for Enhanced Bone Healing in Critical Cases: Traditional bone grafts may not always provide enough structural support or regenerative capacity, especially for complex or large-scale defects. Non-union fracture a fracture that persists for a minimum of 9 months without signs of healing for three months.  Current Treatments for Bone Defects Autografts: Gold standard but limited by donor site morbidity, limited supply. Allografts: Risk of immune rejection, disease transmission. Synthetic bone graft