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    Cells and ECM components are packed together in a random manner. Because of this random character, it is challenging to describe detailed flow pattems on a cellular or subcellular length scale. However, tis possible to characterize and quantify tissue ‘composition if & statistical approach is used, in which larger tissue regions containing many cells are considered. In this ‘case, the average flow rate through the interstitium can be Felated to average interstitial composition by using porous media theory. ‘Since its usually the average flow through a tissue area that is of practical interest, this approach is entirely adequate. ‘These flow pattems are important in fluid clearance but can also have important biological effects. 5.1.4. Darcy's law At tis point, itis necessary to take a small diversion to describe the essentials of porous media theory. A porous material consists of a solid matrix permeated by a network of pores, usually having a very complex topology. Porous media theory is typically used to describe flow through the material when itis too complex or diffcult to describe the flow through ach pore on an individual basis. The basic law describing average flow through the tissue is due to Darcy. In a series of experiments, Darcy forced fluid through porous bodies having crosssectional area A and flow- wise length L. The pressure difference driving flow was. Ap. the Working fluid had viscosity (1, and the resulting flow rate Q was measured (Fig. 6.1). Empirically, Darcy found that his data were correlated by the relationship 5.4.1. Darcy's law ok aul 61) Where, K is a material property called the permeability (or hydraulic permeability), having dimensions of length squared. The permeability is a ppurely local property of the porous ‘material: that is it does not depend on the overall size of the sample being ‘considered. It characterizes the ease with which fluid can pass through the porous material. Sj 5.4.1, Darcy's law Darcy's law is valid only for slow (low Reynolds number) ‘single-phase flow of a Newtonian fluid through a porous matrix. However, that is precisely the situation that occurs when fluid flows through the interstitium, and we therefore take Equation (5.1) as the starting point of a quantitative description of flow in tissue. Noting that QJA is the average (or superficial) velocity of the fluid in the porous material, and that Ap/L is the pressure {gradient in the flow-wise (x) direction, Equation (6.1) can be writen Ka pide 62) where u's the superficial velocity in the x direction 5.4.4. Darcy's law Equation (6.2) can be generalized to three-dimensional flows by replacing (scalar) v and dp/dx with the superficial velocity vector u and the pressure gradient Vp, respectively, to obtain u=->Vp 63) a Equation (53) states that the mean fluid transport rate (u) is ‘proportional to the driving potential Vip, with proportionality constant Kiu 5.1.2. Clearance of edema We will apply Darcy's law to estimate the clearance time of ‘edematous (swollen) tissue, such as a bruise. Everyone is familiar with the concept of bruising: after sustaining blunt trauma, localized swelling and discoloration results, which is cleared over the course of several days. Physiologically, the trauma causes a series of events leading to a loss of capillary endothelial integrity. This allows fluid, plasma proteins, and formed elements to enter the interstitium. ‘The excess fluid produces local swelling (edema). ‘Once the capillary endothelium heals, the surrouncing tissue is left in an overhydrated state. Because significant amounts of plasma protein are present in the edematous tissue, the onoatic pressure in the interstitium is close to that in the capillary, so litle fluid drainage ocours into the capillaries. 5.1.2. Clearance of edema Rather, fuid leaves the edematous tissue by draining into the lymphatic capillaries. We seek to estimate how long it will take the tissue to drain as a function of the properties ofthe interstitium. Evidently a given tissue region will contain many lymphatic capillaries, and, al other things being equal, fluid will drain inta the closest lymphatic capillary. Assuming that al capilaries are similar, itis therefore sufficient to consider a single lymphatic capillary, which we assume is responsible for draining fluid from a cylindrically shaped reaion (or domain of radi 5.4.2. Clearance of edema The entire tissue can be conceptually broken up into such regions, each one draining into its central capilary. The radius of ‘each region will be a function of the number of capilaries per unit volume: more capillaries mean that each capillary must drain a ‘smaller region (smaller R) and mutatis mutandis. To analyze this problem, itis necessary to understand the iving force that causes fuid to leave the tissue. All tissues have ‘an equilibrium or homeostatic level of hydration. The tissue is overhydrated, which causes the ECM components (particularly the proteoglycans) to swell beyond their cequilibrum value. Thermodynamically, it is favorable for the proteoglycans to contract and retum to their equilibrium configuration: in so doing, fluid must be driven out ofthe tissue. 62.2. Drainage of aqueous humor in normal and glaucomatous | ‘8¥€8 The flow of aqueous humor is SHOW indeed: I is produced at only 24 # 016 lin (mean + standard deviation; daytime measurements in adults aged 20883 years). This corresponds to a tumover rate of about 1% of the anterior chamber volume per minute. However, this stow flow is enough to keep the avascular tissues at the front of the eye alive and maintain & pOSiiWe IOP ot approximately 15 mmHg. + How can such a sow flow generate so much pressure? What controls the pressure in healthy eyes so that it stays in @ tity narrow range? + And most importantiy, what goes wrong in gleucoma so that the pressure is elevated? 6.2.2. Drainage of aqueous humor in normal and glaucomatous eyes ‘Most aqueous humor drains through the conventional route, consisting of specialized tissues situated in the angle of the anterior chamber, which is located at the conjunction of the iis, comes, and sclera (Fig. 6.8). Beginning at the anterior chamber and moving 1ese tissues are the trabecular meshwork, @ porous connect tissue; Schlemm’s canal, a collecting duct lined by a vascula-ik endothelium; and the collector channeis/aqueous veins. Ant leaving the aqueous veins, the aqueous humor mixes with blood cleral veins, eventually draining back to the right he 6.22. Drainage of aqueous humor in normal and glaucomatous eyes In the vast majority of glaucomas, the elevation in IOP results from too much aqueous humor drainage resistance, ‘typically owing to changes in the conventional drainage tissues. Let us, therefore, look more closely at the biomechanics of squeous humor drainage from the eye. ‘The aqueous humor can exit the eye bj Aererecsiveree- | Sansa eorvennana route and ie uvec-eclaral (GF UncorveRLora) route. UVEOISGIGH outiow normally carries only about 1085 of total aqueous outflow end is not thought to be the primary site of flow resistance in glaucoma, although it can act as a “safely valve under the right conditions 6.2.2. Drainage of aqueous humor in normal and glaucomatous eyes: |6.2.2. Drainage of aqueous humor in normal and glaucomatous eyes: Direct pressure measurements and circumstantial evidence Indicate that most ofthe flow resistance is inthe trabecular meshwork ff the endothelial lining of Schlemm’'s canal. Since thE aplseleral ‘An early hypothesis about generation of resistance in Glaucoma was that Schlomm's canal could colapse, choking off outflow. This possiblity was considered in detail by Johnson and Kamm, who modeled Schlemm's canal as a compllant channel with 2 porous, elastic wall 162.2. Drainage of aqueous humor in normal and glaucomatous eyes ‘The upper plate, representing the side of Schlemm’s canal that is bounded by the relatively rigid sclera, or outer wall, is immovable. The lower plate, representing the side of Schlernm’s canal adjacent to the trabecular meshwork, or inner wall, is, trabecular meshwoxk stretches, This means that the local “height” of the canal is @ function of position, x, and IOP. permeable and can deform as th 16.2.2. Drainage of aqueous humor in normal and glaucomatous. eyes: Because the canal is highly elongated in cross-section, they treated the channel as two dimensional, that is as being formed by ‘two parallel plates (Fig. 6.9) xo Hl nT a ry gem 6.2.2. Drainage of aqueous humor in normal and glaucomatous | yes The queston is whether Schlem's canal can collapse rough io ceate signifcantfow resislance. The answer 1 tis Ghesion depends on a balanes between ‘wo afect, The sfines (Bastety) of tw Uabecular mestwork tends to Keep the canal pen, wmle the pressure ofop across tre rabeculat mesrwork and inner wall of Scions cara ands 10 free the canal to cova, Any anaiyss of tis process must take these two effects info account The fet eep im he analysis to conserve mass ‘That means that any Tid that enters the canal by crossing the inner wall must increase the local flow rate in the canal, Q(x). The amount of Mid entering the canal depends onthe 1OP, the local pressure wihin the canal, p) and the flow resistance of the trabectlar meshwork and inner wal, Moe speciicaly oro 4) a a 6.2.2. Drainage of aqueous humor in normal and glaucomatous 5 The rghtnand side of Equation (64) represents the rate at which aqueous humor enters Schlomm's canal per unt length of the canal. For convenience, we take X= 0.a3 the midway pont between two collector chanelo, and x= 48 ae the locations ofthe nearest collector channel ost The next stop ie to relate the pressure in Sctlemms canal to the flow in the canal. Because the Reynolds number for flow in Sehlemm’s canal fs 1, we can assume the flow is everywhere unidirectional, so the pressure gfadient in the canal can be ‘obtained from the sition fr laminar flow between paral plates 101) de ei) where i aquecuis humor viseaaly, w isthe depth of the canal into the plane of the page of Fig. 6, and hs) is the local “height ofthe canal 6.2.2. Drainage of aqueous humor in normal and glaucomatous eyes: (65) Equations (6.4), (6.5), and (6.6) represent three equations for the unknowns h(x), p(x), and Q(W. They can be combined to ‘lve a second-order non-linear differential equation, We have to spedily two pieces of boundary data to close the problem. They are that Q(x) = 0 at x = 0 and that p(x) = p,. at +28, where pis the pressure in a collector channel. The resulting system is noninear and a closed form solution is not known; therefore, Johnson and Kamm solved it rumerically. The result is that for reasonable values of the input Parameters, it is predicted that there would be negligible flow resistance within the canal itself, except al extreme pressures (°50, mmHg) when the canal collapses. 16.2.2. Drainage of aqueous humor in normal and glaucomatous ®Y°8 The last step is to account forthe elastcty of the trabecular meshwork. Johnson and Kamm assumed that the trabecular meshwork acted ike a neat aprng, where local deformation was proportional to the pressure drop across the trabecular meshwork. IOP - p(x). More specifically: A-Wls) _10P-n(8) ey h, E where E is the spring stiffness and fh, is the undeformed ‘canal height, corresponding to the case where IOP equals the pressure in the collector channels. (6.2.2. Drainage of aqueous humor in normal and glaucomatous ‘eyes Furthermore, the model predicts that if Schiemm’s canal ‘were nearly collapsed, the resistance of the outfiow sysiem would be a very nonJinear function of IOP, which is not observed experimentally. The conclusion is that Schlemm’s canal collapse does not seem to be important in the normal eye. Even when Schlemm’scanal is largely collapsed at 50 mmbig. the outfiow resistance is less than that seen in glaucomatous eyes, suggesting the glaucoma cannot be explained by collapse of Schlemm's canal How does Schlemm's canal "know" how big to be? We leamed in Section 2.9.1 that large arteries adjust their calber in response to the amount of blood flowing in them of, more specifically, to the shear stress acting on their lining endothelial cells. Perhaps such a mechanism is also operating in Schlemm's canal, The difficulty with this hypothesis is that the flow rate of ‘aqueous humor is 60 low that it seems likely that shear stresses on ‘Schlemm's canal endothelial cells would be very small 6.2.2. Drainage of aqueous humor in normal and glaucomatous | YES We can investigate this further by modifying the collapsible Schlemmn's canal model presented above. Since we know that canal collapse only occurs at very high IOP, let us teat the canal as tigld (non-collapsible) but provide a more realise, Tepresentaton of its geometry in order to improve the estimate of the shear stress on the endothelial cells ining the cara In paticla, instead of modeling the walls of Schlemm’s canal as consisting of two paral plates, we can Leal the canal 28 having an olipical cross-section, with semi-minor axis 2 and semimajor axis b(60e inset Fig. 6.10). In this case, Equation (6.5), is replaces by _ dp _4HQ(s)(I+2*) dx abe 7 162.2. Drainage of equeous humor in normal and glaucomatous '®¥°5 The governing equations are now (6.4) and (6.7), which we can combine to obiain a second-order equation for Q(x). To this we 2 the boundary conditions Q = 0 at x= 0 and Q(x) = Qud2N at x = 48, where Qu is the total aqueous outflow rate and N is the ‘number of collector channels. The solution is: 0, sth(h) sala’) OO) 9 ah (e)" ab Ry swith ke (63) Alingham etal measured the size and cross-sectional area of Schiemm's canal, and from their dala we can compute that i ASSES CSE a = ef glaucomatous eyes. The surprising conclusion is then that the shear strese fe inthe range 2-8 dynesiem’. not too dseimilar from that seen in large arteres 6.2.2. Drainage of aqueous humor in normal and glaucomatous | YES This suggests that shear stresses may have a biological effect on endothelial cells, which is supported by experimental findings that show that Schlemm's canal endothelial cells show preferential alignment. It therefore seems probable that wall shear stress helps to regulate the size of Schlemms canal, and likely has an effect on endothelial cell physiology. It is appealing to think that the celular machinery. for -mechanotransduction and ‘mechenosensing thet work so well in the vascular system have simply been adapted by Schlemm's canal endothelial cells to control Schiemm’s canal calibre ‘What then can explain the relatively large flow resistance associated with the drainage of aqueous humor from the eye? ‘There are two hypotheses. 6.2.2. Drainage of aqueous humor in normal and glaucomatous, eyes ‘There are two hypotheses. It is known that the trabecular meshwork (or more specifically, the region adjacent to Schlemm's canal) contains high ‘concentrations of proteoglycan-tich gels. Modeling has shown that these gels could generate significant flowresistance, and recent data suggest that the tumever of these gel components is modulated by stretch-induced matrix metalloproteinase activity within the trabecular meshwork. The hydraulic permeabilly of ‘many other soft connective tissues with the body is controlled by the concentration of such proteoglycan gels. 6.2.2. Drainage of aqueous humor in normal and glaucomatous 828 There are two hypotheses, + The endothelial ining of Sehlemm’s canal may offer a significant barter to flow. This cellular layer is unusual; for example, it has the highest permeability of any endothelium in the body, with the L24x10“om's/g , yet itis non-fenestrated. The cells are Joined by tight junctions that become more permeable as |OP increases and are permeated by membrane-lined openings (Cpores’) that, although poorly understood, are almost certainly involved in aqueous humor transport 6.2.3. Aqueous humor circulation in the anterior chamber 16.2.3. Aqueous humor circulation in the anterior chamber Before the aqueous humor drains out of the eye it passes through the pupil, traveling from the posterior 10 the anterior chamber, and then circulates in the anterior chamber. Aqueous circulation in the anterior chamber is the result of several stimuli, including blinking, accommodation (changing lens shape to alter focal length), and thermally induced natural convection. Natural convection is interesting and can have clinical implications. It occurs because the comea is normally exposed to ambient air, consequently, the terperature at the posterior corneal surface is sightly less than body temperature. This creates a femperature gradient across the anterior chamber, so that cooler aqueous humor near the corneal surface falls and warmer aqueous humor near the irs rises. (Fig 6.11) 16.2.3. Aqueous humor circulation in the anterior chamber There are several forms of glaucoma in which the elevated OP is not a result of changes in the drainage system of the eye per se. These come under the heading of angle-ciosure glaucoma, a Concition that occurs when the iris pivots forward and blocks access. to the drainage structures in the angle of the anterior chamber. ‘There appears to be an anatomic predisposition to this situation, The itis is extremely pliable, and modeling has shown interesting interactions between iris deformation and aqueous flow through the pupil and between the lens and the iris, especially when the eye is perturbed by blinking 6.2, Biomechanics of glaucoma 6.2.4. Optic nerve head biomechanics Now that we understand IOP, and the fact that its elevated in most forms of glaucoma, we tuin our attention to the optic nerve. Recall that the retinal ganglion cell axons, responsible for canying visual information from the retina to the brain converge from all over the retina to form the optic nerve. How does elevated IOP damage these retinal ganglion cell ‘axons In glaucoma? We do not know the answer to this question, but there is strong evidence that a specialized tissue known as the lamina eribrosa plays an important role in the damage process. The lamina cribrosa is @ porous connective tissue that spans. the scleral canal (Fig. 6.12), mechanically supporting the retinal ganglion cells ofthe optic nerve as they leave the eye. 6.2, Biomechanics of glaucoma 16.2.4. Optic nerve head biomechanics 6.2, Biomechanics of glaucoma 6.2.4. Optic nerve head biomechanics Why do we think the lamina cribrosa is important in glaucoma? To answer this question we need to knowa litle bit about the cellular physiology of neurons. These specialized cells can be subdivided into morphologically and functionally distinct regions, including the call body and one or more elongated processes Known f88 axons. The cell body contains the nucieus and is the site of protein and membrane synthesis, while the axons do not produce proteins. How then can the cell supply its axons, which can be up to several meters in length, with proteins and other substances? Proteins and other materials are transported along axons in vesicles attached to motor proteins that “craw” along the ‘microtubules running within the axons. This process of axoplasmie transport is essential to maintaining the health of the axon. 6.2, Biomechanics of glaucoma 16.2.4. Optic nerve head biomechanics Early studies demonstrated that blockage of this transport Process (‘axoplasmic blockade") occurs when IOP is chronically elevated, and furthermore that this blockade occurs at the level of the lamina eribrosa, Moreover, it is known that lamina cribrosa morphology is, distorted in glaucoma, and that such changes can pre-date the development of ‘vision loss. Finally, the pattern of axon loss correlates with the density of connective tissue in the lamina cribrosa. Such observations have led to much attention being focused on biomechanics of the lamina eribrosa, with the goal of Understanding how elevated IOP leads to retinal ganglion cell damage. 6.2.4. Optic nerve head biomechanics Biomechanically, the lamina crbrosa and scleral canal are very interesting structures. The lamina cribrosa typically consists of approximately 10 ctibiform plates, or lamellae, which contain ‘collagen type IV, laminin, and elastin. Each plate is perforated by between 150 and 600 pores, through which the axonal bundles: run. If we think of the eye as a pressurized spherical shell, then the scleral canal, which is no more than a hole in this vessel, is a site ‘of local stress concentration. The lamina cribrosa, because it is a fairy compliant tissue spanning this canal, is expected to undergo large deformations and Strains as the surrounding sclera deforms. These observations: have led to the machanical theory of glaucomatous optic neuropathy, which postulates that elevated mechanical stresses. acting within the lamina eribrosa lead to axonal damage. 16.2.4. Optic nerve head biomechanics ‘cana 6.2.4. Optic nerve head blomechanics This damage to axons may not be direct, but instead may be mediated through activation of type 18 astrocytes in the lamina cibrosa. Astrocytes are a type of glial cell that function to provide support and guidance to neural calls. When glial cols become activated they proliferate, leading o a glial scar in a process known as gliosis. AS this occurs, the activated astrocytes fal to provide trophic (Le.,nutrtional and appropriate stimulatory) support to thelr surrounding neurons, triggering neuronal death There is a second theory about how retinal ganglion calls are damaged in glaucoma, called the vasogenic theary. It proposes: that the glaucomatous insult results from insufficient vascular Perfusion at the level of the lamina cribrosa, resulting in insufficient 16.2.4. Optic nerve head biomechanics Inadequate autoregulatory function in the branches of the short posterior cllary arteries supplying the laminar region and ‘complications in the hemodynamics of the surrounding vasculature could piay a role in this process [51-54]. There is experimental evidence supporting both the mechanical and the vasogenic theories of glaucomatous damage. and it is probably the case that ‘optic neuropathy results from a combination of both mechanisms. It is also possible that such effects could interact: for example, mechanical deformation of the lamina cfibrasa could lead to Ischemia via distortion of capillary beds. In any case, it should be clear trom the above discussion that we need to better understand the biomechanics of optic nerve hhead tissues, and in particular the biomechanics of the lamina

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