Tissue engineering: Case 6

Pregunta	Respuesta
The need for implants	Ageing population Increased surgeon confidence Increased patient acceptance Governmental regulatory support Improvements in surgical skill Improvements in biomaterials
Implant limitations	Non living: natural tissue can repair itself, implants cannot Failure: post op morbidity/mortality Mis-match in biochemical/mechanical properties: leads to devential failure
Biocompatibility	Shift in materials towards becoming more bioreactive, previously they were mainly bio inert
Classes of biomaterials	Bio-inert: fibrous encapsulation Bio-degradeable: degradeable into natural monomers Bio-reactive: interaction with body tissue (positive stimulatory signals, e.g. to induce growth)
Bioreactivity spectrum: relative bioreactivity of the course of implantation time	Type 1: nearly inert Type 2: porous Type 3: bioactive Type 4: Resorbable
Main causes of hip implant failure	Lack of implant remodeling Stress shielding Contact forces at hip cause fractures Shear stress: load not transmitted to bone Wear between ball and socket from the implant: osteolysis and bone loss
Stress shielding	Stress shielding refers to the reduction in bone density (osteopenia) as a result of removal of normal stress from the bone by an implant (for instance, the femoral component of a hip prosthesis).
Osteochondral regeneration	Drill into bone to release new stem cells to release cartilage stem cells; however, these have the tendency to differentiate into hyaline cartilage as opposed to hyaline cartilage
THR types	Charnley: Co-Cr fem implant. PMMA cemented Charnley type (low friction): THA with metallic femoral component and UHMWPE cup
PMMA: how does it work?	2: 1 powder to liquid mix Creates a pliable putty that can be moulded mis-noma: doesn't actually act as cement Grouting to facilitate implant fixation by wedging
Problems with PMMA	Difficult revision Shrinkage: loosening Osteonecrosis (at end polymerisation) Brittle cement particles can fall into the gap caused on shrinking: wear particle formation --> osteolysis (resorption)
Bioactive coatings	e.g. HA plasma spray onto metal component of implants to allow OB and OCl remodelling to integrate easier revision But runs out Takes long to load bear
Effect of loading environment	High stress concentration/stress shielding: bone resorption around the implant
Aseptic loosening	failure of joint prosthesis withouht presence of mechanical cause or infection: associated with osteolysis/inflammatory response
Wear	there ought to be minimum friction between articular surfaces which leads to reduced wear particle formation wear particles: l
Wear particles: the problem	largest proportion of failed orthopaedic implants Occurs at articulating surfaces and at bone-implant interfaces: leads to osteolysis due to immune reaction leading to failure
Solution to wear: UHMWPE	Reduce implant stiffness to reduce friction High impact strength, bio inert good cyclical fatigue resistance
Problems with UHMPWE	Poor wear resistance Sterilisation reduces properties difficult to process into shape
Solutions	MIS Metal on metal Ceramic on ceramic
Metal-metal: advantages and disadvantages	Biometals: stainles steel/titanium and cobalt alloys (BHAM hip) Advantages: strength, lower wear rate than UHMWPE Disadvantages: Metal wear particles are more toxic
Ceramic on ceramic	Use: femoral head in load bearing in hip prosthesis for younger patients advantages: Very strong, corrosion resistance, good biocompatibility Disadvantages: Squeaking, shatters if there is a crack, heavier
Transplants	Autograft: donor site injury, limited tissue availability Allograft: Immunorejection, lack of donors Xenograft: immune rejection and disease risk
Regeneration over reabsorption: Resorbable bioceramics - degrade over time and be replaced by natural host tissue ( better than autografts?)	Issues: Matching rate of degradation to rate of replacement and strength maintenance of interfaces during bioglass degradation
Bioglass	Combines with bone faster than HA, contains ions that stimulate osteogenesis (Novabone - sensodyne, perioglass)
3D printing of scaffolds	Implanting degradeable scaffold. NB regulatory approval required
Summary: J Jones lecture	THRs: revolutionary, but limited survival + QoL improvement, but to a limited degree Movement towards regeneration over replacement
What is a scaffold?	3D porous temporary template that substitutes the damage tissue and guides the growth of healthy tissue while it is bioresorbed Can be used to trigger and prmote tissue regeneration
What surgeons want - not always what developers make	simple, easy to use, safe Putty/pliability to adapt to body defect Load bearing (ortho)
Ideal scaffold properties for regeneration	Template for tissue growth Porous network (vascularisation, tissue ingrowth, nutrient delivery) Bond to host tissue without scar formation reabsorb at rate of repair Signals to cells to grow
Mechanical properties of a scaffold for bone regeneration	load bearing: share mechanical load with host bone Maintain this during degredation and remodelling Not too ridgid, but not collapsable Strong enough to be handled by surgeons in the operating theatre
Mechanical properties vs biodegradation: scaffolds	Mechanical properties must be maintained during degradation. This should be matched to the rate of growth of the new tissue
Interconnected porosity	vascularisation, cell migration, nutrients and waste diffusion 500 micrometer pores with 100 micrometer interconnection is ideal IF you change one factor, the others will be affected. E.g. increased porosity will weaken mechanical strength
Cartilage structure	Chrondrocytes in lacunae. Cartilage stiffness increases from apical surface to cancellous bone. therefore materials are needed to match the gradient of the stiffness: e.g. Triphasic scaffolds
Challenges with osteochondral scaffolds	Mechanical propeties: gradient of stiffness required (as with normal cartilage structure) Challenges: matching it to this, and ensuring bone fixation Challenge: rate of formation of tissue to rate of degradation of scaffold is different in each individual - difficult to standardise and mass produce Cartilage: avascular: smaller porosity
Biomaterials generations	1st: Allograft based, metals, bioceramics, polymers 2nd: Composites (e.g HA sprayed onto metal) 3rd: Hybrids (shift towards these)
Bioceramics properties	Osteoconductive: cells do note react to it Bio and non-bioresorbable Osteoinductive: ion release that stimulate tissue generation Osteoinductive AND resorbable: Bioactive glasses
Polymers	Natural: good biocompatibility, but poor reproducability and procesability (Collagen, gelatin, chitosan) Synthetic: Good reproducability and biodegradability
Manufacturing techniques	Foaming (like a meringue): application to ceramics and hybrid metals but not mechanically adequate, not reproducable easily, Electrospinning (candyfloss): not weight bearing, but can be used as bone filler 3D printings and robocasting: high specificity and reproducablity, but requires optimising for each technique
Composite	C ombines the advantages of polymers and bioceramics: e.g. HA on metal interface. Inorganic coating of a polymeric skeleton Problems: cell-material interaction and matching degradation rate of matrix and dispersed phase
Hybrids	Combine best properties of organic and inorganic compounds Molecules are bonded at the molecular level: they cannot be distinguished above the nanoscale Problem: matching degradation rates (can be confounded by metabolism and enzymes, etc)
Tissue engineering	Applies principles of life sciences to development of biological substitues that restore, maintain/improve tissue function
Strategies for tissue engineering	Isolated cell or cell substitutes: avoids surgery, but can fail to maintain function/can be rejected Tissue-inducing substances: e.g. synthesis of growth factors to facilitate cell growth (expensive) Cells placed on or within matrices: allows permeation of nutrients and wastes
The need for tissue engineering	Degenerative diseases: OA Severe trauma: challenging natural repair e.g. severe burns - may not be enough tissue to procure grafts Organ transplant: limited availability (the future)
Current treatments for OA	Marrow stimulation Chondral Grafts ACI TKR (late stage): implant failure 15-20 yrs
Whole organ transplantation problems	Long waiting list Donor shortages Immunological suitability IRI: EVLP strategy to preserve, but still has limitations (INSPIRES)
Goal of tissue engineering	create synthetic tissue to take over function of the failing one Treat complex diseases
Three main pillars of tissue engineering	1) cells 2) Scaffolds 3) signalling molecules
ACI limitations	2 stage procedure: cells harvested then expanded in vivo, then re implanted to fill the defect (involves periosteal stripping to patch over the graft). NOT recommended by NICE multiple operatrions, cost and labour intesntive Problems with cell culture: They need to be grown in 3D or they lose ability to resist compression and damage
Adult stem cells	Differentiate, but are more specialised then embryonal stem cells Post-nnatal stem cells have extended self renewable capacity and are multipotent
MSCs	From mesenchymal layer in embryology, are multipotent. Have the tendency to develop specifically into cartilage, heart, neural tissues etc.. Complications: e.g growing nose on back All MSCs are
Tissue specific stem cells	E.g HSCs More specialised than embryonal stem cells, potential solution (e.g. problems in hepatocyte transplantation, not much research into use for cartilage) More research with HSCs
Tissue specific stem cells advantages and disadvantages	Extended self-renewal capacity Multipotent Paracrine signalling potential BUT Heterogeneous population Unreliable results Issue in cartilage repair high variability in chondrogenic differentiation generation of mechanically inferior fibrocartilage
Pluripotent stem cells	Human induced: gene splicing into adult stem cells to convert them back, overcomes ethical considerations, but laborious, take six weeks to develop Embryonic: harvested from the embryo. Indefinite cell renewal, but difficulty to manipulate
Scaffold in tissue engineering	provides structural support, template for cell attachment and matrix formation Architecture influences how cells behave (e.g. pore size, distribution, geometry etc)
Natural matieral scaffolds: collagen, fibrin, hyaluronon	Usually biocompatible/biodegradeable Natural materials: biocompatible, but dificult to process and often have poor mechanical properties
Synthetic matierals: e.g. polymers, ceramics, bioactive glass	Advantages: easier processing, reliable outcome, tailorable properties Disadvantages: Biocompatibility, carefully designed degradation
The importance of scaffold mechanical properties	Scaffold needs to match the mechanical properties of the native tissues in order to effectively carry out function while regeneration occurs. Matched degradation rate ensures that the scaffold does not degrade until the bone is able to take over load bearing Mechanical incompatibility can lead to stress shielding and osteolysis
Growth factors and signalling factors	Singalling factors can be environmental, but other types exist: cell-cell/cell-matrix etc Growth factors: instruct cell behaviour and guide tissue proliferation e.g. TGF- B to prevent cartilage mineralisation
Mechanical stimulation	Bioreactors; mimic in vivo conditions in a closely controlled environment
Environmental factors	Cartilage: Hypoxia essential forchondrocyte differentiation and survival: controls ECM synthesis Bone: HIF 1 alpha accelerates bone regeneration via VEGF for osteogenesis and enchondral ossification
Cartilage regeneration: Composition	Firm elastic CT between bones rib cages etc. Provides biomechanical support Hyaline: T2 collagen, GAGs and water
Cartilage functions	Support and shape Shock absorption Lubricant in joints
Composition of cartilage	Chondrocytes in lacunae: vital for regeneration. Migrate up though cartilage zones, but get older as we do therefore we are unable to maintain it Contain: Collagen, elastin, GAGAs, Calcium and H2O Avascular, a neural, low metabolic rate
Role of ECM in defining mechanical properties of cartilage	Mechanical behaviour of articular cartilage: sponge like Increased charge density (from GAGs) when compressed. Water squeezed out of cartilage

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	Creado por Bhavi Mistry hace más de 8 años