* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download The Eye - CamTools
Survey
Document related concepts
Transcript
Paper 8, Engineering for the Life Sciences Engineering Applied to the Living World: The Eye Timing: Weeks 1-4 Easter term, 2pm-3pm on Mondays, Tuesdays, Thursdays & Fridays Structure: 14 lectures + 2 examples classes (18, 22 May) The aims of the course are to enable students to appreciate the vast potential for the application of engineering principles in biology and medicine, Paper 8, Engineering for the Life Sciences Engineering Applied to the Living World: The Eye Timing: Weeks 1-4 Easter term, 2pm-3pm on Mondays, Tuesdays, Thursdays & Fridays Structure: 14 lectures + 2 examples classes (18, 22 May) The aims of the course are to enable students to appreciate the vast potential for the application of engineering principles in biology and medicine, and learn about four specific application areas in which Part I engineering principles can be applied to: • study the structure and function of the eye. • the design of ocular prostheses. • medical imaging of the components of the eye. • gain insight into visual processing and optimality in eye design 4 Lectures M. Oyen (mlo29) • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy – Eye tissue biomechanics • The Abnormal Eye – Cataracts – Corneal opacity – Myopia, presbyopia • Artificial Materials for Eye Repair – Contact lenses – Intraocular lenses • Tissue Engineering for Eye Repair – Corneal stroma transplants and TE Overview • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy – Eye tissue biomechanics • The Abnormal Eye – Cataracts – Corneal opacity – Myopia, presbyopia • Artificial Materials for Eye Repair – Contact lenses – Intraocular lenses • Tissue Engineering for Eye Repair – Corneal stroma transplants and TE Of what are natural things made, from a materials perspective? Eukarya Animals epithelium muscle tissue connective tissue Plants nervous tissue cells nucleic acids lipids Domain Kingdom epidermis ground tissue vascular tissue ECM proteins Tissue Tissue Components sugars biominerals Molecular Building Blocks Tissues = Cells + ECM • In biology, extracellular matrix (ECM) is any material part of a tissue that is not part of any cell. • Extracellular matrix dominance is the defining feature of connective tissue. epithelial, muscle, and nervous tissue connective tissue Tissues = Cells + ECM • In biology, extracellular matrix (ECM) is any material part of a tissue that is not part of any cell. • Extracellular matrix dominance is the defining feature of connective tissue. • Most connective tissues are: – Involved in structure and support. – Characterized largely by the traits of non-living tissue. – Examples: bone, cartilage, ligaments and tendons epithelial, muscle, and nervous tissue connective tissue Of what are natural things made, from a materials perspective? Eukarya Animals epithelium muscle tissue connective tissue Plants nervous tissue cells nucleic acids lipids Domain Kingdom epidermis ground tissue vascular tissue ECM proteins Tissue Tissue Components sugars biominerals Molecular Building Blocks Macromolecules sugars proteins Cells vs ECM Molecule Sizes Connective Tissue • Cells, proteins, sugars ECM: Proteins and sugars Collagen Y X Gly Hyp often Pro Gly Gly = glycine Pro = proline Hyp = hydroxyproline, a modified form of proline found only in collagen! Collagen The collagen molecule is a triple helix This can be three identical chains: (α1)3 Commonly two and one: (α1)2(α2)1 Collagen http://www.youtube.com/watch?v=NK2VKpVyk2s&feature=related Collagen Cross-linking within a triple helix Cross-linking between triple helices Collagen Types Fibrils and Self-Assembly Typical fibril size 50 nm Graham et al. 2000 (Kadler group) Collagen Julian Voss-Andreae's sculpture Unraveling Collagen (2005), stainless steel. Overview • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy – Eye tissue biomechanics • The Abnormal Eye – Cataracts – Corneal opacity – Myopia, presbyopia • Artificial Materials for Eye Repair – Contact lenses – Intraocular lenses • Tissue Engineering for Eye Repair – Corneal stroma transplants and TE Eye Anatomy Eye Anatomy http://www.jirehdesign.com/eyeanimations/visionEyeAnatomy.htm Tissues in The Eye The connective tissue sclera is continuous with the cornea. The cornea is transparent while the sclera is white (thus the term the “white of the eye”). http://www.youtube.com/watch?v=gvozcv8pS3c&feature=related Tissues in The Eye The crystalline lens sits behind the iris. The overall “eyeball” is called the “globe”. Tissues in The Eye The cornea contributes the majority (2/3) of the eye’s focussing power but is fixed focus. The crystalline lens sits behind the iris and contributes the remainder (1/3) of the eye’s focussing power. Tissues in The Eye: Cornea Cells Collagen and some sugars Cells In humans, the cornea has a diameter of about 11.5 mm and a thickness of 0.5–0.6 mm in the center and 0.6–0.8 mm at the periphery. NB there is no blood supply to the cornea! Anatomy of cornea Epithelium (50 µm) A cornea has 3 main parts. • Stroma has 90% of total thickness and contributes to its toughness & transparency • Collagen fibers + sugar-protein + water Stroma (500 µm) Collagen fibres (30 nm) Endothelium (5 µm) Sugar-protein ground substance Cornea: OF COLLAGEN FIDRILS IN THE HUMAN CORNEA AND 5CLERA / Komoi and Ushiki 2247 cornea d are within ,OOO), Real collagenintertwined fibrilsin aninirregular cross-section (TEM) manner. Those in the pos- ed of successively stacked enfibrils(Figs. 7, 8). These terior region (Fig. 8) were piled up almost parallel to the corneal surface. When specimens were sectioned Corneal Collagen Collagen fibres (30 nm) Sugar-protein ground substance Corneal collagen is crystalline • The collagen fibril diameter is nearly constant • The collagen fibril spacing is regular (and nearly perfect) Corneal collagen crystallinity is crucial both mechanically and optically: • The biaxially aligned collagen adds stiffness to resist the intraocular pressure (IOP) • The regularity of collagen size and spacing results in optical transparency. Corneal index of refraction n = 1.376 Tissues in The Eye Both the cornea and the sclera are made up of collagen and the difference between the two is in the regularity or irregularity of the collagen fibrils. 2254 Cornea: OF COLLAGEN FIDRILS IN THE HUMAN CORNEA AND 5CLERA / Komoi and Ushiki 2247 cornea d are within ,OOO), Collagen fibrils in cross-section intertwined in an irregular manner. Those in the posterior region (Fig. 8) were piled up almost parallel to (side view). the corneal surface. When specimens were sectioned ed of successively stacked enfibrils(Figs. 7, 8). These Sclera: INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / July 1 F TEM ing emp bun (X6 Side view Cornea: 2252 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / J u l y 1991 Vol. 32 Fig. 9. Higher magnification of the lamellar surface of the cornea. Collagen fibrils of each bundle are arranged in the same direction. Small bundles (arrows) extended between lamellae. Fine netlike patterns are observed on the lamellar surface (arrowheads) (X6200). = Top view Collagen fibrils in SEM (Top view). The spatial relationship of adjacent lamellae also is considered to be an important factor for the corneal transparency. Our study showed that the arrangement of the stromal lamellae is more complicated than ex- Cornea: 2252 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / J u l y 1991 Sclera: fore, we consider that stacked lamellae, as a whole, optically act as a single uniform sheet, causing no significant reflections at the surface of individual lamellae. Vol. 32 Fig. 9. Higher magnification of the laFig. 16. A tangential view of the colla-mellar surface of the cornea. Collagen figen bundles in the sclera. Collagen fibril:brils of each bundle are arranged in the run in a wavy fashion and interminglesame direction. Small bundles (arrows) within individual bundles. Note thtextended between lamellae. Fine netlike loose networks of collagen fibrils arouncpatterns are observed on the lamellar the bundles (arrows) (X2700). surface (arrowheads) (X6200). Collagen fibrils in SEM. Alignment of Corneal Collagen Fibrils This simple basket-weave structure is for the central region of the cornea. On the periphery, collagen fibrils are directed towards muscle attachments. Alignment of Corneal Collagen Fibrils NB The eyes are slightly different but mirror images. Tissues in The Eye: Crystalline Lens The cornea and sclera are typical soft connective tissues in the body. In contrast, the crystalline lens is extremely unusual in its composition and structure. Basic lens structure: The lens is about 10 mm in diameter and 3.5-5 mm thick at its center. Tissues in The Eye: Crystalline Lens The lens capsule is typical connective tissue with collagens and sugars. It varies in thickness. Directly beneath the capsule is a layer of epithelial cells. These cells are a source of new lens fibers. Front Back o t Tissues in The Eye: Crystalline Lens The lens capsule is typical connective tissue with collagens and sugars. It varies in thickness. Directly beneath the capsule is a layer of epithelial cells. These cells are a source of new lens fibers. Zonular fibres close to the capsule Capsule Epithelium (transition zone) Lens fibres Front Back [ ] o t Crystalline Lens The bulk of the lens, the cortex (newer fibers) and the nucleus (older fibers), is cellular. These specialized cells are the “lens fibers” and they are vastly elongated lens epithelial cells that have lost most of the normal cell contents (nucleus and organelles). The lens is also 30% protein by mass and the proteins are the very unusual “crystallins”. Zonular fibres close to the capsule Capsule Epithelium (transition zone) Lens fibres [ ] As with the cornea, a large degree of organization is found in the lens and this gives rise to its optical transparency (in a manner that is actually not understood very well). The overall layered structure of the lens fibers is often compared to the layers of an onion. Also in common there are no lens blood vessels. Lens Accommodation • “Amplitude of accommodation” is the max amount that the lens can accommodate in diopters (D), equal to the reciprocal of the focal length measured in metres. Lens Accommodation • The transparent, biconvex lens structure changes shape to change focus. (remember, this controls 1/3 of total focus) • Lens curvature is controlled by ciliary muscles – By changing curvature, one can focus the eye on objects at different distances. – This process is called accommodation. – The lens continually grows throughout life, laying new cells over the old cells = stiffening – The lens gradually loses accommodation ability with age Aqueous and Vitreous Humor The aqueous humor sits in front of the lens and the vitreous humor fills the large part of the globe. Aqueous and Vitreous Humor A V The aqueous and vitreous humors are gels. They consist of proteins and sugars and have very large water contents compared to other soft tissues (98-99% water in VH vs 75% in cornea). The aqueous humor is a a more water-like gel. The vitreous humor is a more solid, gelatinous gel with a loose type II collagen network (recall cornea is type I collagen). Intraocular Pressure The cornea maintains its shape via the pressurized fluid inside the globe. Normal Intraocular Pressure (IOP) is 15.5 mmHg with a range 10-20 mmHg (1 mmHg = 133 Pa) Intraocular Pressure h pR σ= 2h p R € The stress σ in the corneal wall can be approximated via the Laplace Law for a bubble. p = internal fluid pressure (IOP) R = globe radius h = corneal thickness Summary 1a • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy • • • • • Tissues are made of cells + extracellular matrix (ECM) Connective tissues are mostly ECM Soft tissue ECM is water, proteins and sugars Collagen is the most important structural protein Collagen self-assembles from a base unit of the triple helix, into quarter-staggered arrays forming fibrils Summary 1b • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy • Cornea (2/3 of focal power) – Stroma versus cell layers; collagen in sugar-water ground substance – Stromal collagen fibril orientation 0 ± 90° at central cornea – Stromal collagen fibril spacing extremely regular (required for transparency) – Differences between cornea and sclera • Crystalline lens (1/3 of focal power) – Capsule, cortex (anterior and posterior) and nucleus – Specially adapted cells (lens fibers) and proteins (crystallins) – Complicated onion-like layered structure • Vitreous, Aqueous Humors and IOP Overview • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy – Eye tissue biomechanics • The Abnormal Eye – Cataracts – Corneal opacity – Myopia, presbyopia • Artificial Materials for Eye Repair – Contact lenses – Intraocular lenses • Tissue Engineering for Eye Repair – Corneal stroma transplants and TE Tissue Biomechanics • Concerned with baseline structure - (composition) properties relations • Continuum mechanics approaches based on classical elasticity incorporate the “special features” of the mechanical behavior of biological tissues 1. Nonlinear elasticity 2. Anisotropy 3. Time-dependent mechanical responses Tissue Biomechanics 1. Nonlinear Elasticity • Recall typical metal stress-strain response… Tissue Biomechanics 1. Nonlinear Elasticity • Recall typical metal stress-strain response and contrast it with the typical response for a soft biological tissue: Tissue Biomechanics 1. Nonlinear Elasticity • This shape results from the reorientation and sequential “recruitment” of collagen fibrils. • As fibers rotate, there can be deformation with no force • As the fibers reorient, they can then support force • We assume each collagen fibril acts as an elastic spring Tissue Biomechanics 1. Nonlinear Elasticity Reminders from Basic Mechanics From strength of materials σ = Eε F δ =E A L € € F F € F = kδ EA k= L Reminders from Basic Mechanics Springs in series F = F1 = F2 δ = δ1 + δ 2 € Springs in parallel δ = δ1 = δ 2 F = F1 + F2 Reminders from Basic Mechanics Springs in series F = F1 = F2 δ = δ1 + δ2 € Springs in parallel δ = δ1 = δ2 F = F1 + F2 F = kδ = k1δ1 + k2δ2 kδ = k1δ + k 2δ k = k1 + k 2 Reminders from Basic Mechanics Springs in series F = F1 = F2 δ = δ1 + δ2 € 1 1 1 = + k k1 k 2 Springs in parallel δ = δ1 = δ2 F = F1 + F2 F = kδ = k1δ1 + k2δ2 kδ = k1δ + k 2δ k = k1 + k 2 Elastic Recruitment E E E E E The maximum effective stiffness (kmax) or modulus (Emax) is the sum of the stiffnesses of all parallel springs, Emax= n E. Tissue Biomechanics 2. Anisotropy • Because the collagen fibrils are not randomly oriented in 3D, soft tissues are anisotropic like other composite materials. • (IA Materials, composite bounds as in Data Book) Volume Fraction Stiff Phase, Vf Soft Tissue Anisotropy Tissue Biomechanics 3. Time-Dependence Two Mechanisms: 1. These are organic materials, like polymers, so there is bulk viscoelasticity 2. These are hydrated materials, so there is poroelasticity, where time-dependent deformation results from fluid flow. Soft Tissue Viscoelasticity Soft Tissue Viscoelasticity Soft Tissue Viscoelasticity εS = ε D = ε σS + σ D = σ Soft Tissue Viscoelasticity εS = ε D = ε σS + σ D = σ EεS + ηε˙D = σ Eε + ηε˙ = σ τ = η/E Soft Tissue Viscoelasticity εS = ε D = ε σS + σ D = σ EεS + ηε˙D = σ Eε + ηε˙ = σ τ = η/E Limitation: No instantaneous elastic response (no ‘free’ spring): cannot respond to a step change in strain Solution: Soft Tissue Viscoelasticity σ (G1 + G2 ) + σ˙η = G1G2ε + G1ηε˙ € G1 G(t) = G2 + G1 exp(−t /τ )} { G1 + G2 η Instantaneous modulus where τ = G(0) = G1 G1 + G2 Equilibrium modulus G(∞) = G1G2 (G1 + G2)-1 Viscoelastic Extent Viscoelastic Recruitment Viscoelastic Recruitment Poroelasticity → Hydrated biological tissues exhibit time-dependent mechanical behavior in part due to the flow of fluid through a porous elastic or viscoelastic “solid” network. t = 0 t > 0 t >> 0 Poroelastic (Biphasic) E(∞) << 1 E(0) Fluid-like (80% water!) E(∞) = 0.92 E(0) Solid-like Poroelastic (Biphasic) Theory • Simplest form: linear poroelastic theory – Solid phase is linearly elastic and isotropic (E, ν) – All time-dependence is due to flow of fluid through the porous matrix – Effective pore size is typically estimated at nanometre scale – Poroelasticity has three additional material parameters related to the flow and fluid-solid interactions for a total of 5 constants (E, ν, α, β, κ) – α, β, dimensionless and often taken as unity Poroelastic (Biphasic) Theory • Darcy’s Law κA(Δp) Q= h • κ = hydraulic permeability [units m4 (Ns)-1] • Q = rate of volume discharge across an area, A • Δp = pressure gradient applied across specimen with € thickness h Poroelastic (Biphasic) Theory • Time constant h2 τ= Eκ • Intrinsic permeability k = ηκ • η = fluid viscosity (1 mPa s for water) 2 and gives an estimate of the intrinsic pore • k has units of m € size • h = specimen height€ (thickness) • Pore sizes can be too small to see (nm) but can be measured mechanically Intrinsic permeability Various analytical and computational models exist for relating permeability (k) to microstructure (fiber size, a, and solid fraction, φ): k = a 2 f (φ ) Langmuir Happel Jackson & James 1 $ 3 φ2 ' f (φ ) = &−ln(φ ) − + 2φ − ) 2 2( € 4φ % 1 $ φ 2 −1 ' f (φ ) = &−ln(φ ) + 2 ) 8φ % φ +1 ( * 1 -' 3 $ f (φ ) = /) &−ln(φ ) − 0.931+ O, 20φ % + ln(φ ) .( Jackson and James, Canadian J. Chem. Eng. 64 (1986) 364-74. Intrinsic Permeability Scaling Laws Langmuir Happel Jackson & James Mechanical Testing of Cornea Test parameters: Force, displacement, time Test parameters: Pressure, shape, time Geometry: Width, length, thickness Geometry: Radius, thickness Excision of strip for tensile testing Ends are attached to tensile grips Strip Extensometry Test Set-up Thickness variation in strips Corneal strip extension tests • There is clear evidence of the nonlinearity of response • Rupture occurs atan axial force of between 23 and 26 N. • Behaviour beyond 16 N (not shown) remains approximately linear at the maximum stiffness until rupture. How to mechanically test corneal tissue? • Strip extensometry (tensile) test – Dissect strip of corneal tissue – Inherent challenges: • Strip is from spherical surface – centerline is longer than along sides • Flattening of curved specimen – Initial compressive and tensile strains – Compressive stresses cause reduced tensile stresses under external tensile loading • Corneal thickness increases with distance from center Corneal Inflation Test Set-up Last Revised on: 5/2/12 MCEN 4134 / 5228 Biomechanics 85 Corneal Inflation Tests • Long phase of linear behaviour followed by gradual stiffening at ~15–30 mmHg Comparing strip extension and inflation test results • On average, the strip tests overestimate the material stiffness by about 32% compared with the inflation test procedure. • Mathematically account for: (1) Standard approach 31% (2) Consider length variation 17% (3) Consider flattening of initial curvature 5% (4) Consider thickness variation % difference from (1) Mechanical Testing of Cornea Pros: Simple and fast to execute, analyze Can obtain some anisotropy information Pros: More physiological 3D information Cons: Uniaxial deformation does not reflect cornea biaxial loading in vivo Cons: Difficult to execute Requires models to interpret Summary 2 • The Normal Eye – Eye tissue biomechanics • Nonlinearity – Spring recruitment models Emax • Anisotropy – Composite bounds Eupper and Elower • Time-dependent deformation: viscoelasticity – Spring-dashpot models G(0) and G(∞) • Time-dependent deformation: poroelasticity – k = a2 f (Φ) • Uniaxial and biaxial mechanical testing of cornea Overview • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy – Eye tissue biomechanics • The Abnormal Eye – Cataracts – Corneal opacity – Myopia, presbyopia • Artificial Materials for Eye Repair – Contact lenses – Intraocular lenses • Tissue Engineering for Eye Repair – Corneal stroma transplants and TE Lens Accommodation muscles Myopia, Hyperopia, Presbyopia Myopia = nearsightedness, an inability to view distant objects in focus; this is corrected with concave lenses Myopia, Hyperopia, Presbyopia Hyperopia and Presbyopia = farsightedness, an inability to view close-up objects in focus; this is corrected with convex lenses Myopia, Hyperopia, Presbyopia Myopia and Hyperopia are genetic but Presbyopia is part of the aging process and happens to nearly everyone. The near point is the closest object that can be brought into focus naturally. This ranges from a few cm in children to an arm’s length in advancing middle age to beyond an arm’s length in old age Lens Biomechanics There appears to be no protein turnover in the nucleus throughout lifespan. – The lens is thus prone to age related changes. – Lens stiffening with age inhibits accommodation. Mechanical Testing of Lens • • • • • Indentation testing of lens across the surface Tested 8 points across lens Three rows when possible 1mm spacing Calculate Shear Modulus, G (Pa), from: where: P = total load (N) R = indentor radius (m) d = maximal depth of penetration (m) ν = Poisson’s ratio Stiffness profile across young and old lens YOUNG HUMAN LENS OLD HUMAN LENS Observe the difference in magnitude of G !!! Stiffness changes with age Nucleus (interior) and cortex (exterior) of lens both become substantially stiffer with increasing age. (again note Log scale!) Lens Geometry Changes with Age The lens becomes larger with age, in addition to becoming stiffer. LASIK Surgery Laser-Assisted In Situ Keratomileusis Recall that 2/3 of the eye’s focussing power comes via the cornea. LASIK is used to re-shape the cornea to restore vision. • The cornea is opened in a “flap” to expose the stroma • A laser is used to vaporize regions of the corneal stroma • The flap is closed and naturally re-adheres (no sutures are required) This is a cornea-based fix to a lens- (accommodation) based problem. LASIK patients cannot be cornea donors. http://catalog.nucleusinc.com/generateexhibit.php?ID=32886&ExhibitKeywordsRaw=&TL=&A=2 Contact Lenses The idea started percolating through the medical and scientific community in the first half of the 20th century Types of lenses (Elastic modulus): • Glass 1880s-1930s (70 GPa) • PMMA 1930s-80s (4 GPa) “rigid” • Silicone acrylates (gas permeable) 1980s-90s (~GPa) • Silicone rubbers1960s (1-10 MPa) • Hydrogels 1970s-present (kPa-MPa) Cornea elastic modulus: 1-15 MPa depending on location, orientation Advances in contact lens materials technology have made them increasingly cheap and disposable over the years. € Hydrogel Contact Lenses A hydrogel is a water-swollen polymer network, that can be up to 99% water by volume (recall the cornea is approximately 75% water) A hydrogel’s properties are largely defined by the volume fractions of polymer and water within the material, as defined by a swelling ratio, Q, which is in turn related to the most important gel physical characteristic, the mesh size ξ Vswollen Q= Vdry € ξ ∝ Q1/ 3 Determinants of Swelling Ratio Determinants of the swelling behavior: l type and concentration of monomers (nature of the hydrogel polymer network) l cross-link density l temperature, pH during network formation l ionic strength of fluid (salts) Swelling (Q) a.k.a. mesh size (ξ) determines the mechanical stiffness, strength and permeability Bottom line: Hydrogels demonstrate a trade-off between relatively poor mechanical properties and excellent biocompatibility, in both cases due to the large water content! Corneal Opacity Corneal opacity is similarly a cloudy (opaque) cornea. This is most often (but not exclusively) due to injury, inflammation or infection, and thus sudden in onset compared with the gradual deterioration of the lens in cataracts. The best current fix is a corneal transplant (increasingly difficult to find donors). Corneal Transplants • There exists a need for a material to act as the corneal stroma, to allow for re-creating the cell layers on both surfaces to better mimic a real cornea – It would be a bonus if the material would “heal” into the surrounding healthy tissue Corneal Transplants • In cases of corneal opacity, transplants from donor eyes are very successful – As with all transplant surgeries, there is a risk of rejection – There is also a significant shortage of donor corneas, waiting lists are up to two years and likely to increase significantly since eyes with LASIK surgery are unusable as donors • There have been some precedents of polymeric materials (PMMA, in particular) used for corneal transplants, especially in cases of a failed cornea transplant. – Complications include induced glaucoma, extrusion of the implant, and inflammatory reactions – These tend to be very invasive procedures, not just involving the cornea itself but invading the globe substantially Amniotic Membrane Grafts November 2008 • Amniotic membrane graft for eye surgery • 100+ microns thick http://www.iopinc.com/news/ambio5-launch/ Artificial cornea project: Flexicornea Polymethylmethacrylate (PMMA) - non-degrading - First human use in 2009 Thickness: central 0.3 mm, skirt 1 mm. Dr. Joachim Storsberg Fraunhofer institute Cataracts A cataract is defined as a cloudy (opaque) lens. This is extremely common in the elderly and is a leading cause of blindness in people of all ages in the developing world. Cataract Surgery • Artificial intraocular lenses (IOLs) are implanted after removal of the cloudy lens (cataract) in a very common surgery (10,000,000 IOLs implanted per year) http://catalog.nucleusinc.com/generateexhibit.php?ID=34654&ExhibitKeywordsRaw=&TL=&A=2 Intraocular Lens Materials • Early intraocular lenses were PMMA (E ~ 4 GPa) • Modern acrylate lenses are flexible so as to be folded for the surgical insertion; these include both hydrophobic and hydrogel polymers. In addition to acrylates, silicone rubber has been used. (E ~ 3 MPa) Intraocular Lens Materials • Although first done in 1950, the procedure gained significant popularity in the 1970s with improved IOL materials • Modern lenses are significantly lighter as well, 20 mg on average compared with 110 mg for early PMMA lenses • The reduction in stiffness associated with the modern, flexible lenses allowed for a change in surgical procedure for a minimally-invasive approach requiring no stitches – Recovery is much faster – Outcomes are significantly approved • IOL materials are often doped with UV absorbing additives to protect the retina from radiation damage • Historically IOLs are monofocal—accommodation is lost Intraocular Lens Future • Cataracts are an enormous problem in the developing world: it is estimated that 35 million more operations could take place a year compared with the 10 million currently • Multi-focal and accommodating IOLs are currently under development for improving on monofocal IOLs – A word of caution is warranted here: in many types of medical implants, the earliest designs and simplest principles have proven more effective than “advanced” designs • In the future, advanced IOLs may be used to correct vision defects, instead of glasses, contacts, or LASIK – “Phakic” IOLs are like permanent contact lenses implanted between the cornea and iris Overview • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy – Eye tissue biomechanics • The Abnormal Eye – Cataracts – Corneal opacity – Myopia, presbyopia • Artificial Materials for Eye Repair – Contact lenses – Intraocular lenses • Tissue Engineering for Eye Repair – Corneal stroma transplants and TE Tissues = Cells + ECM • The living parts of tissues are the biological cells • Solid polymers, or even hydrogels, replace only part of a tissue that is diseased or injured—the ECM • This has resulted in the frequent favoring of transplant technology where living cells are included (heart, liver) • The new field of tissue engineering aims to use polymers or hydrogels as artificial ECM and to seed this artificial ECM with living biological cells connective tissue Tissue Engineering !"##$%&'()"(%%*"() ! +%(%*,-&./%0%1& ! ! 2(#.%,3&45&*%6-,7"()&3%5%7."8%&."##$%#&9"./&0,(: 0,3%&3%8"7%#;&.*<&.4&*%:)*49&/%,-./<&."##$%#&=< & ! 0,>"()&-"8"()&"06-,(.#&9"./&,7."8%&7%--# Corneal Tissue Engineering Tissue Engineering Cells Scaffolds Tissue Engineering Bioreactors Signals Corneal Tissue Engineering Tissue Engineering Cells Scaffolds Tissue Engineering Bioreactors Signals Tissue Engineering and Scaffolds Corneal Tissue Engineering Two routes to implantation: • Implant a cell-scaffold construct • Grow the cell-scaffold construct in vitro prior to implantation Tissue Bioreactors (a) Spinner flasks (b) Rotating wall vessels (c) Hollow fibre perfusion (d) Direct flow perfusion (e) Direct compression Different benefits to each in terms of nutrient transfer, mechanical stresses Closed-loop Tissue Engineering? For scaling up the process for widespread use, many additional issues will have to be considered including sterilization, labeling, automation Tissue Engineering and Scaffolds Corneal Tissue Engineering Cells Scaffolds Scaffolds (porous frameworks) • Naturally-derived Tissue Engineering – Collagen, collagen-GAG • Polymeric – Can be biodegradable (PLGA) • Apatite (bone, teeth replacement) • Hydrogels • Self-assembled or Fabricated Bioreactors Signals Tissue Engineering and Scaffolds Corneal Tissue Engineering Scaffold architecture and tunable properties – Composition – Porosity – Permeability – Isotropy or anisotropy – Stability/resorption rate – Ease of manufacture – Stiffness – Strength – Cytocompatibility Advantages of scaffold-based systems – Greater initial mechanical properties – 3D structure to grow large tissue samples Disadvantages of scaffold-based systems – Permanent exogenous materials or clearance of degradation byproducts may affect performance ScaffoldTissue Mechanical Design Corneal Engineering Scaffold porosity involves a mechanical optimization E porous E solid # " porous & 2 !% ( $ " solid ' Esolid and relative density are the tunable initial parameters. Scaffold transport behavior –Ratio of Permeability to Porosity !/! –Related to pore interconnectivity –Tissue formation is often on surface only Electrospinning Static target Gelatin solution 15kV Needle Syringe pump Voltage generator Electrospinning set-up for random fibres Gelatin solution Gelatin fibres 15kV Needle Rotating mandrel Syringe pump Voltage generator Electrospinning set-up for aligned fibres Natural collagen Electrospinning http://nano.mtu.edu/Electrospinning_start.html Electrospun fibres Natural collagen Corneal Tissue Engineering • True corneal tissue engineering is still “of the future” although research is being actively pursued across the world due to the increasing scarcity of donor tissue • Current challenges include: – poor mechanical properties of man-made stromal matrices – poor optical transparency of man-made stromal matrices • Tissue engineered constructs are currently seen as an excellent mechanism for studying corneal tissue in the laboratory, without having an imminent clinical application Corneal Tissue Engineering Tissue Engineering Cells Scaffolds MUCH MORE IN Tissue Engineering MODULE 3G5: BIOMATERIALS NOW IN MICHAELMAS Bioreactors Signals Summary 3 • The Abnormal Eye – Cataracts – Corneal opacity – Myopia, presbyopia • Artificial Materials for Eye Repair – Contact lenses – Intraocular lenses • Tissue Engineering for Eye Repair – Corneal stroma transplants and TE • Hydrogels • LASIK surgery • Electrospinning That’s All, Folks! • The Normal Eye – Composition and structure of biological tissues – Normal eye anatomy – Eye tissue biomechanics • The Abnormal Eye – Cataracts – Corneal opacity – Myopia, presbyopia • Artificial Materials for Eye Repair – Contact lenses – Intraocular lenses • Tissue Engineering for Eye Repair – Corneal stroma transplants and TE Examples Class 18 t h May