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25 March 2010

ARTICLE IN PRESS

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Mathematical Biosciences

journal homepage: www.elsevier.com/locate/mbs

2 Review

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3

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5 a

Department of Chemical Engineering, University of Patras, GR-26504 Patras, Greece

6 b

Institute of Chemical Engineering and High Temperature Chemical Processes (ICEHT), GR-26504 Patras, Greece

7 Q2 c

Foundation of Research and Technology, Hellas (FORTH), GR-70013 Heraklion, Crete, Greece

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a r t i c l e i n f o a b s t r a c t

1 4

2 0

11 Article history: Fluid–structure interactions strongly affect, in multiple ways, the structure and function of cellular bio- 25

12 Received 30 August 2009 logical media, such as tissues, bioﬁlms, and cell-entrapping gels. Mathematical models and computer 26

13 Received in revised form 10 March 2010 simulation are important tools in advancing our understanding of these interactions, interpreting exper- 27

14 Accepted 12 March 2010

imental observations, and designing novel processes and biomaterials. In this paper, we present a com- 28

15 Available online xxxx

prehensive survey and highlight promising directions of future research on theoretical modeling of 29

16

17

Keywords:

Fluid–structure interactions

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momentum transport in cellular biological media with focus on the formulation of governing equations

and the calculation of material properties both theoretically and experimentally. With regard to the gov-

erning equations, signiﬁcant work has been done with single-scale approaches (e.g. mixture theory),

30

31

32

18 Hierarchical multiscale modeling

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19 Material properties whereas traditional upscaling methods (e.g. homogenization, volume averaging) or multiscale equa- 33

20 Hydraulic permeability tion-free approaches have received limited attention. The underlying concepts, strengths, and limitations 34

21 Bioﬁlm of each approach, as well as examples of use in the ﬁeld of biomaterials are presented. The current status 35

22 Tissue of knowledge regarding the dependence of macroscopic material properties on the volume fractions, 36

23

geometry, and intrinsic material properties of the constituent phases (cells, extracellular matrix and 37

ﬂuid) is also presented. The observation of conformational changes that occur at ﬁner levels of the struc- 38

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tural hierarchy during momentum transport, the correlation of macro-properties with geometrical and 39

topological features of materials with heterogeneous and anisotropic microstructure, as well as the deter- 40

mination of dynamic material properties are among important challenges for future research. 41

Ó 2010 Published by Elsevier Inc. 42

43

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44

45 1. Introduction lar ﬂuid and the deformable solid matrix (cells plus extracellular 61

matrix) plays multiple important roles: (a) affects the internal 62

46 Fluid–structure interactions in cellular biological media, such as architecture (spatial arrangement of cells and EPS) and the external 63

47 tissues, artiﬁcial cell-entrapping gels, microbial ﬂocs, and bioﬁlms, morphology (overall size and shape) of the cellular biological med- 64

are of great importance in quite diverse ﬁelds of science and tech- ium (e.g. [6]), (b) enhances the mass transfer rate of chemical spe-

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48 65

49 nology, including medicine, biology, biotechnology, tissue and cies (nutrients, wastes, chemical signaling molecules, etc.) within 66

50 environmental engineering. In particular, the theoretical analysis the cellular biological medium [1,7–10], and (c) regulates the func- 67

51 of momentum transfer during the ﬂow of the extracellular ﬂuid tion of cells through the action of mechanical stresses, which are 68

52 is necessary in many technological applications and natural pro- either applied directly on the outer surface of the biological cell, 69

53 cesses, such as the in vitro construction of artiﬁcial tissues from hu- or transmitted indirectly through the extracellular polymeric ma- 70

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54 man stem cells in order to replace damaged tissues [1], the trix [11–15]. 71

55 biodegradation of organic contaminants by microbial bioﬁlms in Among the ﬁrst contributions highlighting the role of ﬂuid ﬂow 72

56 porous media [2], the settling and consolidation of suspended in enhancing solute transport through convection in tissues is the 73

57 microbial ﬂocs in solid–liquid separation processes [3], the forma- work of Swabb et al. [7], who showed that the relative importance 74

58 tion of microbial cakes on membrane ﬁltration units [4], and the of convective versus diffusive mass transfer depends strongly on 75

59 delivery of chemotherapeutic agents to malignant tumors [5]. In the glycosaminoglycan (GAG) content of the tissue and the size 76

60 all these processes, the interaction between the ﬂowing extracellu- of solute molecules. Larger solutes and lower GAG content result 77

in convection dominated mass transfer. In a similar vein, Piekarski 78

* Correspondence to: G.E. Kapellos, Department of Chemical Engineering, and Munro [16] suggested that the cyclic mechanical loading in 79

University of Patras, Karatheodori Str. 1, GR-26504 Patras, Achaia, Greece. Tel.: bone causes signiﬁcant pulsatile ﬂow in the canalicular network, 80

+30 2610 996 219; fax: +30 2610 990 328. which in turn results in enhanced mass transfer. Further informa- 81

E-mail addresses: gek222@chemeng.upatras.gr (G.E. Kapellos), xalexiou@chem

tion on the ﬂow enhanced mass transfer in the interstitial space of 82

eng.upatras.gr (T.S. Alexiou).

1

Deceased.

tissues is given in [17]. 83

doi:10.1016/j.mbs.2010.03.003

Please cite this article in press as: G.E. Kapellos et al., Theoretical modeling of ﬂuid ﬂow in cellular biological media: An overview, Math. Biosci. (2010),

doi:10.1016/j.mbs.2010.03.003

MBS 7041 No. of Pages 11, Model 5G

25 March 2010

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84 In addition, over the last 30 years, signiﬁcant evidence has accu- scribe the mechanical behavior of cells and tissues, in [30] for com- 150

85 mulated to support the role of interstitial ﬂow in stimulating tissue putational modeling of cell spreading and tissue growth, in [31] for 151

86 growth and regeneration. Perhaps, the ﬁrst paradigm of this role is ﬂow within the vascular network. As pointed out in the stimulating 152

87 the increase of bone mass under electromechanical stimulation, review by Humphrey [28] and also advocated here much work re- 153

88 where the coupling between electrical and mechanical forces is ef- mains to be done. 154

89 fected by streaming potentials developed during the ﬂow of the io- The purpose of this paper is to present a comprehensive survey 155

90 nic aqueous solution in the canalicular network of bone [18,19]. of the literature pertinent to the theoretical analysis of momentum 156

91 Another interesting example is the work by Sikavitsas et al. [20] transfer in cellular biological media with focus on the formulation 157

92 who clearly showed that ﬂuid shear affects strongly the osteogenic of governing equations and the calculation of material properties. 158

93 activity of osteoblasts growing in artiﬁcial scaffolds within perfu- Promising directions of future research are also highlighted. This 159

94 sion bioreactors. Speciﬁcally, by increasing the viscosity and keep- work was necessitated by the ever-growing interest on modeling 160

95 ing constant the ﬂow rate of the feed solution, they achieved to ﬂuid–structure interactions in cellular biological media over the 161

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96 increase the ﬂuid shear while maintaining practically constant last decade and the lack of a relevant review in the literature. 162

97 the mass transfer ﬂuxes in the bioreactor. It was observed that

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98 the increased shear resulted in increased deposition and more uni-

99 form spatial distribution of mineralized matrix in the scaffold. Re- 2. Cellular biological media 163

100 cent advances on the ﬂow-induced regulation of cellular functions

101 and mechanotransduction (i.e., translation of a physical force to The analysis of transport processes requires knowledge of the 164

102 the corresponding intracellular signal) within various tissues are detailed composition, structure, and even function of the cellular 165

103 reviewed in [12–15]. biological medium under consideration. A bioﬁlm is a microbial 166

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104 With regard to microbial cellular biological media, the analysis consortium embedded in a three-dimensional meshwork of extra- 167

105 of interstitial ﬂow has been of prime interest in ﬁltration and sep- cellular polymeric substances (EPS), which is swollen in an aque- 168

106 aration processes. Notably, the extracellular ﬂow affects strongly ous environment, and is usually immobilized on a solid surface 169

107 the settling velocity of suspended microbial ﬂocs, as well as the ﬁl- [32,33]. The EPS hydrogel is composed mainly of polysaccharides 170

108 tration efﬁciency of membranes covered by microbial cakes and (e.g. alginates, xanthan, cellulose) and proteins, which accumulate 171

109 bioﬁlms [3,4]. On the other hand, the effects of extracellular ﬂow D in the extracellular space, primarily by active secretion from the 172

110 and mechanical stresses on cell functions and bioﬁlm growth have microbial cells and as residues from cell lysis [34]. A microbial ﬂoc 173

111 received limited attention. For example, the interesting work of is quite similar to a bioﬁlm, but it differs in that it is found sus- 174

112 Fowler and Richardson [11], who showed that forced extracellular pended in an aquatic environment rather than attached on a solid 175

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113 ﬂow increases the metabolic activity of Escherichia coli cells, has surface. Finally, a tissue is an organized population of eukaryotic 176

114 been ignored in the literature. cells all of which perform the same functions. The conﬁned space 177

115 The analysis of the mechanics and ﬂuid–structure interactions between tissue cells is known as the interstitial space (or interstit- 178

116 in cellular biological media requires a multidisciplinary approach ium) and contains ﬂuid and an extracellular meshwork of proteins 179

117 integrating knowledge from mathematics, biology, biophysics, bio- (collagen, ﬁbrin, elastin) and GAG (also referred to as EPS hydro- 180

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118 chemistry along with engineering principles. Our understanding of gel). Many tissues also contain a network of blood microvessels 181

119 the complex physical and biological mechanisms has grown by and a network of lymphatic microvessels. Here, we conﬁne our 182

120 using more sophisticated and more accurate experimental tools attention to the extravascular space, which contains the cellular 183

121 (e.g. magnetic resonance imaging, computed micro-tomography, and interstitial spaces. 184

122 confocal laser microscopy), which allow one to study these pro- Despite the existence of signiﬁcant differences in the detailed 185

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123 cesses with a narrow observation window in space-time and, thus, composition, structure and function of different types of cellular 186

124 track phenomena and behavior associated even with single cells or biological media, they all exhibit a hierarchical structure, which 187

125 single biomacromolecules. For example, Liu et al. [21] combined evolves in time and presents a high degree of spatial organization 188

126 atomic force with ﬂuorescence microscopy to study the mechani- at every characteristic length-scale. There exist at least three fun- 189

127 cal properties of individual ﬁbrin ﬁbers. Interestingly, they found damental scales of observation with characteristic lengths deﬁned 190

128 that ﬁbrin ﬁbers can be stretched to nearly three times their nor- by the diameter of the extracellular polymeric ﬁbers (several nm, 191

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129 mal length without loosing elasticity and up to six times before P-scale), the size of a single biological cell (a few lm, K-scale) 192

130 rupturing. and the size of the overall cellular biological medium (from 193

131 Measurable progress has been achieved in the development of tenths of lm to a few cm, B-scale). For instance, Fig. 1 schemat- 194

132 mathematical models and computer-aided simulators, which are ically illustrates these three fundamental scales of the structural 195

133 valuable tools for the elucidation of the underlying mechanisms hierarchy of a microbial bioﬁlm. Note that we use the term scale 196

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134 and the prediction of the process under consideration. The ﬁrst to denote the spatial dimension of an object or process character- 197

135 models accounting for the coupling between ﬂuid ﬂow and matrix ized by both extent and resolution [35, p. 29]. The term extent de- 198

136 deformation in tissues appeared in the early 80s and were based on notes the overall size of the observable area or volume. The term 199

137 Biot’s poroelasticity [19] and mixture theory [22]. Over the last resolution denotes the size of the smallest discernible element of 200

138 three decades, these theories have been further developed and re- area (pixel) or volume (voxel). Both extent and resolution depend 201

139 ﬁned to account for ﬁnite deformations, electrokinetics, and other on the instrument which is used to make the observation. One 202

140 features of the physical systems [23–25]. Recently, upscaling very important feature of the physical systems under consider- 203

141 methods, such as volume averaging and homogenization, were ation is the large separation of characteristic length-scales. Thus, 204

142 used to connect the macroscale description to microscale structure it is feasible to deﬁne the dimensions of a voxel, which is associ- 205

143 and function of cellular biological media (e.g. [26]). These works ated with a point on a coarse spatial scale, to be sufﬁciently large 206

144 were focused mainly to verify and deﬁne the validity domain of to include all the phases present at the ﬁner spatial scale, and 207

145 the equations used in poroelasticity and mixture theories, but also much smaller than the extent of the coarse spatial scale. This fea- 208

146 to provide means for the theoretical calculation of constitutive ture allows one to implement standard upscaling methods (vol- 209

147 parameters. Comprehensive discussions on various aspects of ume averaging, homogenization, etc.) in order to derive a 210

148 modeling momentum transport in cellular biological media are macroscale description of the process from the corresponding 211

149 provided in [27–29] with regard to constitutive models used to de- governing equations at ﬁner spatial scales. 212

Please cite this article in press as: G.E. Kapellos et al., Theoretical modeling of ﬂuid ﬂow in cellular biological media: An overview, Math. Biosci. (2010),

doi:10.1016/j.mbs.2010.03.003

MBS 7041 No. of Pages 11, Model 5G

25 March 2010

ARTICLE IN PRESS

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Fig. 1. Schematic representation of the hierarchical structure of a microbial bioﬁlm.

213 3. Formulation of the conservation equations and constitutive into account the effects of anisotropy, viscoelasticity for the solid 242

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214 relations matrix, and inertia for the ﬂuid (a summary of his work can be 243

found in [37]). Biot’s theory of poroelasticity has been used to 244

215 An integrated theoretical analysis of any such process requires predict the mechanics of bone [19,38], brain [39], solid tumors 245

216 dealing with two fundamental issues. The ﬁrst issue regards the [40–42], and polymeric hydrogels [43,44]. In passing, we mention 246

217 formulation of the continuity and momentum conservation equa- that other phenomenological theoretical approaches for deform- 247

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218 tions as well as the necessary constitutive relations at the cellular able porous media have been developed for the process of cake 248

219 biological medium scale of observation (B-scale). The second issue ﬁltration (e.g. [45,46]). 249

220 regards the proper connection of the parameters, which appear in The theory of mixtures was developed for the mathematical 250

221 the constitutive equations, with the geometrical parameters and description of momentum, mass, and energy transport in multi- 251

222 the physicochemical parameters that pertain to the phenomena component, multiphase systems at a scale of observation with res- 252

223 taking place at the molecular- and cell-scales of observation. With olution much larger than the characteristic length of the individual 253

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224 regard to the formulation of the momentum conservation equa- constituents and phases (the structure of the system at ﬁner spatial 254

225 tions and the necessary constitutive relations at the cellular biolog- scales is disregarded completely). The mathematical foundation of 255

226 ical medium scale (B-scale), we distinguish three fundamentally the theory was originally set by Truesdell [47], and relies upon the 256

227 different routes of theoretical analysis, which are presented below. concept that the constituents of the mixture can be modeled as 257

superimposed, interacting continua. In this way, a material point 258

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228 3.1. Single-scale approaches occupied by the mixture. The governing conservation laws for each 260

constituent of the mixture contain the usual terms (that appear in 261

229 One commonly used approach is to disregard the ﬁner spatial formulations for a single-phase), and an additional term which ac- 262

230 scales of the physical system and formulate these equations di- counts for the interaction between the reference constituent and 263

231 rectly on the B-scale. In this direction, the theoretical analysis of the other constituents of the mixture. Exhaustive reviews on the 264

232 momentum transfer in cellular biological media and biological theory of mixtures are given in [48,49]. Mixture theory was intro- 265

233 hydrogels has been based mainly on Biot’s theory of poroelasticity, duced in the ﬁeld of biomaterials by Mow et al. [22], in their sem- 266

234 as well as on the theory of mixtures combined with a thermody- inal work on the mechanical behavior of cartilage. They showed 267

235 namic approach. Motivated by the problem of soil subsidence, Biot that a biphasic mixture theory (linearly elastic solid, Newtonian 268

236 [36] formulated a phenomenological theory on the consolidation of ﬂuid) captures very well the experimentally observed behavior of 269

237 deformable porous media saturated with a ﬂuid. In that pioneering articular cartilage under conﬁned compression. In order to achieve 270

238 work, he considered the porous medium as homogeneous and iso- this agreement between theory and experiment it was necessary to 271

239 tropic at the macroscale, and treated the solid matrix as a linearly express the permeability of the cartilage as a function of the solid 272

240 elastic solid and the ﬂuid, which occupies the pore space, as incom- dilatation. Another key ﬁnding of their work is that tissue-scale 273

241 pressible and Newtonian. Later, he extended his theory by taking viscoelastic behavior (creep, stress relaxation) can be observed as 274

Please cite this article in press as: G.E. Kapellos et al., Theoretical modeling of ﬂuid ﬂow in cellular biological media: An overview, Math. Biosci. (2010),

doi:10.1016/j.mbs.2010.03.003

MBS 7041 No. of Pages 11, Model 5G

25 March 2010

ARTICLE IN PRESS

275 a result of the relative motion between the two constituents, even The formulation of the conservation laws and constitutive equa- 334

276 if none of the constituents is viscoelastic. Thereafter, the theory has tions directly on the B-scale is of limited value because of the ab- 335

277 been extended and used widely to predict the mechanics of carti- sence of cross-scale consistency and, in many cases, because of 336

278 lage [23–25], endothelial glycocalyx [50], solid tumors [51,52], the ambiguous correspondence between theoretical dependent 337

279 hydrogels [53], soft tissues in general [54–59], and ﬁlter cakes variables and experimentally measured quantities. In addition, sin- 338

280 [60]. In the simplest case, a cellular biological medium can be con- gle-scale approaches do not provide a consistent theoretical frame- 339

281 sidered as a biphasic mixture which consists of a linearly elastic so- work for the calculation of the constitutive parameters and, 340

282 lid constituent (cells plus EPS meshwork) and a Newtonian ﬂuid usually, leave this task for the experimenter. 341

283 constituent (extracellular aqueous solution). In the framework of

284 mixture theory, signiﬁcant effort has been made to incorporate 3.2. Multiscale bottom-up approaches 342

285 electrokinetic phenomena (for example, the triphasic mixture the-

286 ory of Lai et al. [23]), as well as non-linear phenomena, including An approach that is more versatile and robust than the single- 343

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287 the dependence of the permeability on solid dilatation [25], ﬁnite scale ones is to develop the governing equations on the B-scale 344

288 solid deformation [25,57], and viscoelastic behaviour [53,56]. A starting from ‘‘well-established” ﬁrst principles on the K- or even 345

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289 comprehensive presentation of the equations that describe ﬂuid the P-scale. For this purpose, one can implement mathematical 346

290 ﬂow and matrix deformation in a cellular biological medium, in procedures, including the spatial homogenization method (e.g. 347

291 the context of Biot’s theory of poroelasticity and the theory of mix- [26,71]) and volume averaging methods (e.g. [72–77]), which were 348

292 tures, is given in Appendix A (this also facilitates the comparison initially applied to the analysis of transport phenomena and 349

293 with the equations established using the spatial averaging method mechanics of porous or composite materials, in the context of con- 350

294 in a companion paper [61]). tinuum mechanics. 351

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295 In many cases, it is possible to decouple extracellular ﬂuid ﬂow These upscaling methods offer two signiﬁcant advantages over 352

296 and solid matrix deformation and, thus, model the two processes in single-scale approaches. First, one can obtain precise correspon- 353

297 a sequential fashion. This decoupling hypothesis is applicable, for dence between theoretical variables deﬁned at different spatial 354

298 example, if the solid matrix behaves as an elastic solid (that is, re- scales, as well as between theoretical variables and the respective 355

299 sponds instantaneously to the applied stress), or if the ﬂow-in- experimentally measured quantities (via the use of appropriate 356

300 duced deformation of the solid matrix is negligible. Along this D weight functions in the averaging procedure). Second, a framework 357

301 direction, the theory of Newtonian ﬂuid ﬂow through rigid porous is provided for the linkage of constitutive parameters deﬁned at 358

302 media has been adopted for the description of ﬂow through sus- the coarse spatial scale with the structure of and the phenomena 359

303 pended microbial aggregates (e.g. [62–64]), bioﬁlms [65], and the occurring at ﬁner spatial scales. Thereby, a direct comparison be- 360

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304 extravascular space of tissues (e.g. [66–68]). tween theory and experiment can be accomplished without the 361

305 Finally, many single-scale models incorporate (usually, use of adjustable parameters. In any case, the derived upscaled 362

306 ‘‘silently”) the perfect coupling hypothesis, according to which all momentum balance equations (inclusive of the constitutive rela- 363

307 the constituent phases of the system move with the same average tions) should meet two prerequisites. First, these must contain 364

308 velocity and, thus, a monophasic description is employed. Under this only measurable average variables (density, pressure, velocity, dis- 365

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309 hypothesis, momentum transfer in a cellular biological medium, at placement) and a minimum number of physically meaningful con- 366

310 the B-scale of observation, follows the formulation of conservation stitutive parameters (elastic moduli, hydraulic permeability, etc.). 367

311 laws and constitutive equations for single-phase materials. In the Second, the velocity (or displacement) ﬁeld in the cellular biologi- 368

312 tissue literature, it is common to adopt the theory of elasticity or vis- cal medium, which is obtained from the solution of the upscaled 369

313 coelasticity for the description of tissue mechanics [28,29]. Analo- momentum equations, should be identical to the ﬁeld that would 370

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314 gous examples from the bioﬁlm literature include the work by be obtained if a complete description at the molecular scale was 371

315 Dupin et al. [69], where the bioﬁlm is modelled as a highly viscous feasible. This prerequisite is usually veriﬁed through comparison 372

316 Newtonian ﬂuid, and the work by Towler et al. [70], where the bio- with data from well-controlled experiments. 373

317 ﬁlm is modelled as a Burgers viscoelastic ﬂuid. Limited work has been made up to now in the analysis of trans- 374

318 Using order-of-magnitude analysis in the context of the spatial port processes in cellular biological media using multiscale ap- 375

319 averaging method, we have obtained the following conditions proaches. To our knowledge, the ﬁrst decent efforts in this 376

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320 which delimit the domain of validity of the biphasic and monopha- direction were made in the ﬁeld of bone mechanics by Crolet 377

321 sic (elastic or viscoelastic) models for the macroscopic description et al. [78] and Hollister et al. [79], both of which applied the spatial 378

322 of momentum transport in a ﬂuid–solid system (linearly elastic so- homogenization method to derive macroscopic equations and cor- 379

323 lid, Newtonian ﬂuid) [61]. relate the apparent elastic moduli of the bone with the microstruc- 380

uf lf ture. The collagen and hydroxyapatite, which compose the bone, 381

IF ¼ O½1 THEN monophasic viscoelastic

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! agreement was observed between theory and experiment, in terms 383

kp s2s;c uf lf of the apparent elastic moduli. However, the importance of inter- 384

IF þ 1 << << 1 THEN monophasic elastic

uf ‘2p s2s u s ls ss stitial ﬂuid ﬂow was not fully appreciated at that time and, thus, 385

!

u f lf keff s 2 ﬂow effects were not included in the models. Signiﬁcant work 386

s;c

IF < þ1 THEN biphasic model has been made by Wood and Whitaker [80–82] who used a volume 387

us ð2ls þ ks Þss uf ‘2p s 2

s

325 averaging method to derive the macroscopic equations that de- 388

qﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ

2

ﬃ scribe solute diffusion and reaction, cell growth, and EPS produc- 389

326 with: ss;c ¼ ð2lqssþk

‘p

sÞ

. tion in bioﬁlms at the B-scale of observation, starting with a 390

327 Here, uf is the volume fraction of ﬂuid, us is the volume fraction continuum-based formulation at the cell-scale. They developed a 391

328 of solid, lf is the dynamic viscosity of the ﬂuid, ls ; ks are the Lamé closure scheme for the calculation of the diffusion coefﬁcient ten- 392

329 parameters for the solid, qs is the density of the solid, kp is the sor, and observed good agreement between theoretical predictions 393

330 hydraulic permeability of the ﬂuid–solid system, ss is the charac- and experimentally determined values. However, an empirical ap- 394

331 teristic time for changes in the displacement of the solid (e.g. per- proach was introduced for the rate of accumulation of cellular 395

332 iod of harmonic oscillation), and ‘p is the characteristic length of mass that is caused by convection in order to circumvent the com- 396

333 the system on the macroscopic scale. plex problem of momentum transport. The spatial homogenization 397

doi:10.1016/j.mbs.2010.03.003

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398 method was used by Moyne and Murad [26] to derive the steady- expected to become useful tools in the study of systems with 462

399 state equations that govern ﬂow and deformation in cartilage, at non-linear material behavior. 463

400 the macroscale. The aqueous solution that occupies the pore space

401 of the cartilage was considered as Newtonian, and the ﬁber net-

4. Calculation of the constitutive parameters 464

402 work as a linearly elastic solid. It should be noted that the presence

403 of ions in the aqueous solution and surface charge on the ﬁbers

The calculation of the parameters that appear in the constitutive 465

404 were taken into account. The upscaled equations obtained via the

equations, which describe the behavior of the material at the B-scale 466

405 homogenization method are similar in form with those formulated

of observation, can be performed either experimentally or theoreti- 467

406 in the triphasic mixture theory of Lai et al. [23]. Nonetheless, Moy-

cally. For the studied process, constitutive parameters of interest ap- 468

407 ne and Murad did not proceed with the theoretical calculation of

pear in the expressions for the stress tensors (viscosity of the 469

408 the constitutive parameters which appear in their model. Recently,

extracellular ﬂuid, elastic moduli of the solid matrix), and the inter- 470

409 we used the spatial averaging method via a weight function to

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action force between the extracellular ﬂuid and the EPS-plus-cells 471

410 establish the equation which describes solute conservation at the

matrix (hydraulic permeability). These material properties depend 472

411 B-scale, starting with a continuum-based formulation of solute

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on the phenomena and the structure observed at ﬁner spatial scales. 473

412 transport at ﬁner spatial scales [83]. An effective-medium model

For the problem at hand, the uncovering of the correlation between 474

413 was developed for the calculation of the diffusion coefﬁcient, in

microstructure and macro-properties is a challenging task, both in 475

414 consistence with the averaging method. The model predicted the

theory and experiment, because conformational changes occur at 476

415 qualitative trend as well as the quantitative variability of a large

every level of the hierarchical structure during momentum 477

416 number of published experimental data on the diffusion coefﬁcient

transport. 478

417 of oxygen in cell-entrapping gels, microbial ﬂocs, bioﬁlms, and

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418 mammalian tissues. In a companion paper, we use the spatial aver-

419 aging method to establish the equations governing momentum 4.1. Experimental determination of constitutive parameters 479

420 transfer in cellular biological media, and develop theoretical mod-

421 els for the calculation of the hydraulic permeability [61]. The experimental determination of constitutive parameters can 480

be achieved by ﬁtting the outcome of a theoretical model to the 481

422 3.3. Multiscale computational, constitutive-equation-free approaches corresponding measurements from well-controlled experiments. 482

D The suitable experimental method usually differs for different

types of cellular biological media. For instance, the hydraulic per-

483

484

424 logical medium cannot be captured satisfactorily over a wide range meability has been estimated with infusion [87–89], compression 485

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425 of working conditions using well-established, simple constitutive [90,91], or perfusion experiments [88,92,93] for tissues, with set- 486

426 equations. Single-scale methods usually rely on heuristic ap- tling experiments for suspended microbial ﬂocs [9,94], and with 487

427 proaches, which stem from the modeller’s experience along with ﬁltration techniques for microbial cakes and bioﬁlms formed on 488

428 trial-and-error, so as to extend the validity range of existing consti- the surface of porous membranes [4,95–100]. Note that in the tis- 489

429 tutive models. Further, the implementation of standard upscaling sue literature, the term infusion refers to localized delivery of ﬂuid 490

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430 methods, such as homogenization and volume averaging, becomes to a tissue from a point source (i.e., the tip of a needle or a catheter), 491

431 a formidable task if there exist material components which exhibit while the term perfusion refers to the delivery of ﬂuid from a sur- 492

432 non-linear mechanical behaviour at the ﬁner spatial scale or, if face source with dimensions comparable to the tissue dimensions. 493

433 there does not exist a large separation of characteristic length- An issue of crucial importance is to ensure that the determined 494

434 scales (which is necessary in order to perform signiﬁcant simpliﬁ- constitutive parameters are independent of the speciﬁc procedure, 495

RR

435 cations in the calculus). Over the last decade, a new line of analysis measuring device, and specimen size used in the experiments. This 496

436 has been developed for the study of complex systems with hierar- issue is frequently overlooked. The inﬂuence of these factors 497

437 chical structure: the so-called equation-free approach [84]. The should be minimized by choosing an appropriate experimental 498

438 main idea of the equation-free approach is to circumvent the for- method and, further, taken into account explicitly in the formula- 499

439 mulation of macroscopic constitutive equations and calculate the tion of the theoretical model for the process. The inﬂuence of the 500

440 quantities of interest at the macroscale by performing appropri- measuring process can be represented mathematically using 501

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441 ately initialized computational simulations at the microscale. A weight functions, which allow one to obtain a precise correspon- 502

442 representative elementary volume (REV), which contains a geo- dence between theoretical dependent variables and the respective 503

443 metric representation of the structure at the microscale, is assigned experimentally measured quantities, as well as to relate experi- 504

444 to every macroscale point or, in practice, to every element of the mental measurements obtained with different techniques [101]. 505

445 macroscale computational mesh. Regarding the conceptual frame- Another robust approach to account for the effect of the measuring 506

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446 work of the equation-free approach, the establishment of direct process and sample size is the computer-aided simulation of the 507

447 handshaking for bidirectional information transfer between two experimental test (virtual experiment). Some noteworthy exam- 508

448 scales is of crucial importance. There is no golden rule for the suc- ples in this direction include the simulated compression test on a 509

449 cessful cross-scale linkage. Local information from the macroscale tissue specimen by van Rietbergen et al. [102] for the calculation 510

450 must be properly projected to the microscale and used to deﬁne of the elastic moduli, the simulated perfusion experiment by John- 511

451 appropriate boundary and initial conditions (downscaling). Then, son and Deen [103] for the estimation of the hydraulic permeabil- 512

452 computational simulation of the process is performed, in the con- ity of hydrogels, and the simulated infusion experiment by 513

453 text of the REV, for a given period of time and the distributions of Milosevic et al. [89] for the estimation of the hydraulic permeabil- 514

454 microscale quantities are properly averaged to obtain the values of ity of tissues in vivo. 515

455 the corresponding macroscale quantities at that point or element The endmost goal is to obtain a correlation between the constitu- 516

456 (upscaling). The upscaling step is achieved using theorems estab- tive parameter of interest and other measurable properties of the 517

457 lished in the context of the homogenization or volume averaging system. In principle, this correlation should involve only features 518

458 methods. In the ﬁeld of biomechanics, equation-free approaches of the structure and composition at ﬁner spatial scales. However, 519

459 have been developed to predict the mechanical response of tissue in practice it is very difﬁcult (if feasible) to follow-up the conforma- 520

460 constructs [85] and collagen networks [86] under compression, tional changes that occur at every level of the hierarchical structure 521

461 omitting the ﬂow of the extracellular ﬂuid. Such approaches are during the experimental test and, thus, it is customary to correlate 522

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523 the constitutive parameters with other macroscopic quantities, such crease of the elastic and shear moduli [78,106] and in a decrease of 587

524 as the apparent density of the cellular biological medium [104], the the hydraulic permeability [105,107]. 588

525 dilatation/strain of the solid matrix [22–24,93], and the pressure Equally important is the effect of the intrinsic material proper- 589

526 gradient of the extracellular ﬂuid [4]. Relatively few experimental ties of the constituent phases which, however, are usually difﬁcult 590

527 studies have presented data regarding the quantitative correlation to determine from independent experiments. An issue that should 591

528 between the mechanical properties (elastic moduli and hydraulic be examined carefully concerns the effect of the spatial variability 592

529 permeability), the composition, and the microstructure of a cellular in the material properties of the constituent phases. Using a com- 593

530 biological medium. Most of those studies have demonstrated that putational homogenization approach Sengers et al. [112] found 594

531 the volume fractions of the constituent phases (cells, EPS, water) that the hydraulic permeability and the elastic modulus of an arti- 595

532 strongly affect the mechanical properties [90,91,98,100,105]. More- ﬁcial tissue construct are to a large extent insensitive to the EPS 596

533 over, comprehensive studies on ﬂuid ﬂow through beds of biological distribution at the cell-scale of observation. Only in the case of very 597

534 cells have shown that the hydraulic permeability depends markedly localized pericellular deposition did the elastic modulus take sig- 598

F

535 on the size, shape, and orientation of cells [95,98–100], as well as on niﬁcantly lower values than those in the case of homogeneous dis- 599

536 the gelatinous sheath that covers the cells [97]. tribution of the same amount of EPS in the extracellular space. The 600

OO

hydraulic permeability was not affected even though appreciably 601

537 4.2. Theoretical calculation of constitutive parameters different ﬂow patterns were obtained for each case (Fig. 4 in 602

[112]). Recently, we developed a theoretical model for diffusive 603

538 The theoretical calculation of a constitutive parameter requires mass transfer in cellular biological media [83] and showed that 604

539 the development of: (1) a structural model, which provides the the diffusion coefﬁcient obtains substantially different values for 605

540 internal geometry and topology of the cellular biological medium the two extreme cases of homogeneous distribution and pericellu- 606

PR

541 with sufﬁciently high spatial resolution, (2) a process model, which lar deposition of the EPS. The difference between the two bounding 607

542 mathematically describes the momentum transport in the context values depends on the volume fraction of extracellular space, the 608

543 of the structural model, and (3) a closure scheme, which links math- porosity of the EPS hydrogel, and the size of diffusing species and 609

544 ematically the value of the constitutive parameter with the struc- EPS ﬁbers. In a companion paper [61], we elaborate further on this 610

545 tural and process models used for the ﬁner spatial scale. issue with respect to the hydraulic permeability. 611

546 With regard to the structural model we distinguish three differ- D The characteristic dimensions, shape and spatial arrangement 612

547 ent approaches. The simplest approach is to consider the cellular of the component material elements (cells, EPS ﬁbers, and pores) 613

548 biological medium as an ensemble of (geometric) unit cells also affect the mechanical properties of a cellular biological med- 614

549 [78,79,83,106–111]. Each unit cell represents the structure in the ium signiﬁcantly. For instance, Beno et al. [109] presented a theo- 615

TE

550 vicinity of a few biological cells. A more realistic approach is to rep- retical model for the hydraulic permeability of cortical bone, and 616

551 resent the cellular biological medium as a regular or random array concluded that the canalicular and osteocyte process dimensions, 617

552 of biological cells [112]. Finally, the most promising approach is to the geometry of the GAG matrix (interﬁber spacing and ﬁber ra- 618

553 use digitized images of real cellular biological media, which can be dius) that partially occupies the canaliculi, as well as the lacuna–la- 619

554 obtained using three-dimensional reconstruction from two-dimen- cuna distance have a strong effect on the permeability. Also, they 620

EC

555 sional serial sections, confocal laser scanning microscopy (CLSM), suggested that the osteocyte lacuna shape and size, along with 621

556 X-ray computed micro-tomography (micro-CT), or any other suit- the three-dimensional distribution of canaliculi, determine the de- 622

557 able visualization technique. Up to date, this approach has been gree of anisotropy of the permeability. 623

558 used for the prediction of bone mechanical properties [102,113] The architecture of the EPS matrix is a key determinant of the 624

559 but it is expected to become very popular and useful for all types permeability of the cellular biological medium. The problem of 625

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560 of cellular biological media in the near future. ﬂow through ﬁbrous materials is well-studied and there exist 626

561 With regard to the process model we distinguish two different several models that can be used to obtain estimates for the 627

562 approaches. In the ﬁrst approach, a constituent phase is treated as intrinsic permeability of the EPS hydrogel as a function of ﬁber 628

563 a continuum at the ﬁner spatial scale and momentum transport volume fraction and arrangement (see Table 1; for further read- 629

564 (ﬂuid ﬂow and solid matrix deformation) is described with a set ing see the reviews [118–120]). A simple and useful correlation 630

565 of partial differential equations, which can be solved analytically has been proposed by Jackson and James [118]. Speciﬁcally, they 631

CO

566 or numerically depending on the complexity of the adopted struc- considered that for randomly oriented ﬁbers the resistance ex- 632

567 tural model. In the second approach, a constituent phase is treated erted by the solid matrix on ﬂuid ﬂow can be estimated by 633

568 as a population of interacting agents (ﬂuid and solid particles, adding the resistance resulting from ﬁbers oriented with their 634

569 mass-and-spring elements, molecules, etc.) and momentum trans- axis normal to the macroscopic ﬂow direction to the resistance 635

570 port is described using computer-aided simulations, such as spring resulting from ﬁbers oriented with their axis parallel to the mac- 636

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571 network analysis, molecular dynamics and other, in the context of roscopic ﬂow direction. The possibility that a ﬁber axis is ori- 637

572 statistical mechanics. With regard to the closure scheme, several ented normal to the ﬂow is twice that of being parallel to the 638

573 different approaches have been developed in the literature, ﬂow. Therefore, the total resistance equals 2/3 of the resistance 639

574 including heuristic REV analysis [106–109], effective-medium resulting from normal orientation plus 1/3 of the resistance 640

575 approaches [83,110,114], asymptotic homogenization [78,79,111– resulting from parallel orientation 641

576 113], and volume averaging [83,115].

1 2 1

577 Considerable work has been done for the prediction of the elas- ¼ þ

kp 3kp? 3kp== 643

578 tic properties of tissues, especially of bone and cartilage (e.g.

579 [78,79,102,106,110,111,113,114,116]). On the other hand, limited where kp? is the permeability for ﬁbers oriented normal to the mac- 644

580 work has been done for the hydraulic permeability [107– roscopic ﬂow direction and kp== is the permeability for ﬁbers ori- 645

581 109,112,117]. In general, the mechanical properties (elastic moduli ented parallel to the macroscopic ﬂow direction. Jackson and 646

582 and hydraulic permeability) of a cellular biological medium de- James used the results of [121] for the calculation of kp? and kp== . 647

583 pend on the volume fractions, geometry, topology, and intrinsic The ﬁnal expression is 648

584 material properties of the constituent phases at ﬁner spatial scales.

kp 3

585 In particular, the effect of the volume fractions is prominent. An in- ¼ ½ ln us 0:931

586 crease in the volume fraction of solids (EPS, cells) results in an in- r2fiber 20us 650

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Table 1

Theoretical models for the permeability of ﬁbrous porous materials.

Jackson and kp

¼ 3

½Inur 0:931 Combination of analytical solutions

r 2p 20ur

James [118]

Davies [124] kp

¼ 1 Fit to a large number of data for the ﬂow of air through ﬁbrous materials

r 2p 3=2

ð1þ56u3r Þ

16ur

Johnston [125] h i2 Fit to experimental data for ﬂow through disordered ﬁbrous materials

kp

r 2p

¼ 0:01064 ð1uruÞð2ur Þ

r

Koponen kp 5:55

¼ expð10:1 Fit to data from the simulation of ﬂow in disordered ﬁbrous structures with the lattice-

r 2p u r Þ1

et at. [126] Boltzmann method

Clague kp

1 pﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ 2 Fit to data from ﬂow simulations in periodic arrays with the LB method

r 2p

¼ c1 2 p=ur 1 expðc2 ur Þ

et al. [123] c1 ¼ 0:50941; c2 ¼ 1:8042 (square) c1 ¼ 0:71407; c2 ¼ 0:51854 (random)

h i

Happel [127] u2r Cylinder in cell model. Analytical solution (\ denotes ﬂow normal to the ﬁber axis)

F

kp?

r 2p

¼ 8u1 ln ur 1

1þu2r

r

h i

Happel [127] kp==

¼ 4u1 ln ur 32 þ 2ur 2r

u2 Cylinder in cell model. Analytical solution (// denotes ﬂow parallel to the ﬁber axis)

r2p r

OO

Kuwabara [128] kp?

¼ 8u1 ln ur 32 þ 2ur Cylinder in cell model. Analytical solution

r 2p r

Sangani and kp?

¼ 8u1 ln ur 1:476 þ 2ur 1:774u2r þ 4:076u3r Periodic square array

r2

p r

Acrivos [129]

Sangani and kp?

¼ 8u1 ln ur 1:490 þ 2ur 1:5u2r Periodic hexagonal array

r 2p r

Acrivos [129]

h i

Drummond and kp== u2

¼ 4u1 ln ur þ K DT þ 2ur 2r KDT = 1.476 (square array)

r2p r

Tahir [121]

PR

KDT = 1.498 (trigonal array)

KDT = 1.354 (hexagonal array)

Drummond and kp?

¼ 8u1 lnur 1:476 þ 2ur 1:774u2r þ 4:078u3r Periodic square array

r 2p r

Tahir [121]

pﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ

Gebart [130] kp?

¼ ð16=9pc1 Þ½ ur: max =ur 15=2 Analytical solution for periodic arrays based on lubrication approximation

r 2p pﬃﬃﬃ pﬃﬃﬃ pﬃﬃﬃﬃﬃﬃ

ðc1 ; ur;max Þ ¼ ð 2; p=4Þ (square) ðc1 ; ur;max Þ ¼ ð 6; p= 12Þ (hexagonal)

Gebart [130] kp==

¼ c82 ð1uu2r Þ

3

c2 ¼ 57 square arrangement

r2p r D

c2 ¼ 53 hexagonal arrangement

TE

651 where r fiber is the EPS ﬁber radius, and us is the ﬁber volume frac- macroscopic material properties and heterogeneous, anisotropic 688

652 tion. The above equation provides satisfactory agreement with a microstructures characterized by wide distributions of geometrical 689

653 large number of experimental data for ﬂow through ﬁbrous materi- (size and shape), topological (e.g. connectivity, orientation), and 690

654 als (including hydrogels of acrylamide, hyaluronic acid, collagen other properties (e.g. electrical charge) at the cell- or EPS-scale. 691

655 [118]). Further, a comparison the data from numerical simulations

EC

657 the model of Jackson and James provides reliable estimates of the 5. Perspectives for future work 692

658 permeability in the range 0:10 6 us 6 0:20, whereas underesti-

659 mates the permeability for very small ﬁber volume fractions. From the literature survey becomes obvious that signiﬁcant 693

660 The mechanical behavior at the surfaces of separation between work has been done, but much remains to be done in the future. 694

RR

661 different contiguous phases is another important factor. Schwartz Multiscale approaches, which take into account the process and 695

662 et al. [110] developed a theoretical model for the elastic moduli structure at ﬁner spatial scales of the hierarchal structure of cellu- 696

663 of articular cartilage and showed that the shear modulus depends lar biological media, create a premise for improved modeling of 697

664 strongly on the extent of slipping between collagen ﬁbers and the momentum transfer and ﬂuid–structure interactions at the macro- 698

665 surrounding proteoglycan matrix (which might be caused by scopic B-scale (which is the scale of practical interest). Some prom- 699

666 imperfect bonding between the two materials). ising directions for future research are given below: 700

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668 and within bulk phases has also a noticeable effect. Eisenberg Derivation of the governing equations using traditional upscal- 701

669 and coworkers [107,108] developed a theoretical model for the cal- ing methods, such as spatial averaging and homogenization. 702

670 culation of the hydraulic permeability of the extracellular matrix The coupling of hydrodynamics with electrokinetics, osmotic 703

671 (EPS hydrogel) taking into account the electrohydrodynamic cou- and other phenomena should be addressed. 704

pling caused by the interaction between mobile charged species Incorporation of advanced non-equilibrium thermodynamic

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672 705

673 dissolved in the ﬂowing aqueous solution and immobile charged frameworks, which account to a certain extent for the micro- 706

674 species located at the surface of the EPS ﬁbers. They showed that structure (e.g. via a conformation tensor), in single-scale 707

675 the hydraulic permeability depends on the surface charge density, approaches (‘‘microstructured mixture theory”). 708

676 as well as on the salt concentration in the bulk aqueous solution. Development of multiscale equation-free approaches for sys- 709

677 The degree of dependence is substantial for the open-circuit per- tems with non-linear mechanical behavior at the microscale. 710

678 meability (zero net electric current) and minor for the short-circuit Usually, such approaches should be tailored to a speciﬁc cellular 711

679 permeability (zero gradient of electrical potential) in consistence biological medium. Among other issues, the inclusion of hydro- 712

680 with experimental observations. Furthermore, Mattern and Deen dynamics, and comparison of different schemes for cross-scale 713

681 [117] showed that the distribution of surface charge density has handshaking should be addressed. 714

682 a marked effect on the open-circuit permeability. Comparison between different theoretical approaches in a fair 715

683 Admittedly, theoretical modeling has shed signiﬁcant light on context, that is for a given system under a common set of 716

684 the dependence of macroscopic constitutive parameters on micro- assumptions and boundary conditions. For instance, under what 717

685 structural features. However, some important issues have not been conditions are the equations obtained via homogenization 718

686 addressed yet. For instance, it deserves to use more realistic and equivalent to a mixture theory formulation, for a cellular bio- 719

687 complex structural models to examine the correlation between logical medium with macroscopic heterogeneities? 720

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ARTICLE IN PRESS

721 Conduction of well-controlled experiments that will provide the where reff is the ‘‘effective” stress tensor for the entire material 786

722 material properties (if possible, all the components of the ten- (ﬂuid plus solid), u is the displacement of the material, P is the ﬂuid 787

723 sors) along with information about the composition and pressure, e ¼ r u is the material dilatation, v is the ﬂuid velocity, 788

724 microstructure, under quasi-steady-state conditions. The deter- leff and keff are the Lamé parameters, lf is the ﬂuid viscosity, keff 789

725 mination of the material properties alone is of little or no use. is the permeability of the material, h is the variation of the ﬂuid 790

726 Determination of dynamic material properties under transient volume fraction (‘‘variation in water content”), and a; M are phenom- 791

727 conditions both experimentally and theoretically. These are enological coefﬁcients (also known as Biot or Biot–Willis coefﬁ- 792

728 expected to be substantially different from quasi-steady state cients). Substituting the constitutive Eq. (A2) in the momentum 793

729 values. This task will require the use or development of appro- balance (A1), and combining with the Eqs. A3, A4 and A5 we obtain 794

730 priate imaging techniques and computer simulation methods

731 for the determination of the conformational changes that occur leff r2 u þ leff þ keff re arP ¼ 0 ðA6Þ

732 at ﬁner levels of the structural hierarchy during momentum @e 1 @P keff 2

F

733 transport. The deﬁnition of proper measures for the quantiﬁca- a þ r P¼0 ðA7Þ

@t M @t lf 796

734 tion of geometrical and topological features of the structure of

OO

735 cellular biological media at ﬁner characteristic spatial scales In [131] a worthy effort is made to attribute a clear physical 797

736 (cell-, EPS-) should also be addressed. meaning to the coefﬁcients a and M, and methods for their exper- 798

737 Consideration of the inﬂuence of specimen geometry (size, imental determination are proposed. For example, the coefﬁcient a 799

738 shape) and experimental measuring device via the use of expresses the ratio of the variation of pore volume to the dilatation 800

739 weight functions and/or virtual experiments. of the solid, under constant total volume conditions. Usually, the 801

740 Use of more realistic and complex structural models to examine ﬂuid and the solid matrix are considered to be intrinsically incom- 802

PR

741 theoretically the dependence of the macroscopic material prop- pressible and, thus, the values a ¼ 1 and 1=M ¼ 0 are used [39–42]. 803

742 erties and their degree of anisotropy on the statistical and spa- In this case we have 804

743 tial distributions and correlations of geometrical (e.g. cell size 805

744 and shape), topological (e.g. interstitial connectivity, cell orien- leff r2 u þ leff þ keff re rP ¼ 0 ðA8Þ

745 tation), and other properties (e.g. EPS permeability, electrical @e keff 2

r P¼0 ðA9Þ

746 charge) of the structure at the cell- or EPS-scale. @t lf 807

747

D By taking the divergence of (A8) we obtain [39] 808

748 In a companion paper we present work in some of the directions

749 mentioned above. In closing, it should be mentioned that although

2leff þ keff r2 e ¼ r2 P ðA10Þ

TE

810

750 transport phenomena in cellular biological media can be treated in

751 a uniﬁed manner, speciﬁc solutions should be tailored to speciﬁc Therefore we can equivalently express Eq. (A9) as follows: 811

752 applications with different types of cellular biological media. The 812

753 processes of cell growth and matrix production were beyond the @e keff

¼ 2leff þ keff r2 e ðA11Þ

754 scope of this work and deﬁnitely deserve to be treated in detail @t lf 814

EC

755 separately.

It is important to note that the equations formulated by Biot di- 815

rectly on the macroscopic scale, are similar to those obtained by 816

756 Appendix A. Elements of Biot’s theory of poroelasticity and applying the method of spatial homogenization [71] and the meth- 817

757 mixture theory od of spatial averaging [75] to the equations that hold at the scale 818

of pores and grains.

RR

819

758 A.1. Biot’s phenomenological theory for poroelastic materials

759 A cellular biological medium can be considered as a poroelastic

760 material, which consists of an elastic solid matrix (cells plus EPS

In the simplest case, a cellular biological medium can be consid- 821

761 meshwork) and well inter-connected pores that are occupied by

CO

762 the extracellular ﬂuid solution. In the context of the initial Biot the-

(cells plus EPS network) and a ﬂuid constituent (extracellular 823

763 ory for poroelastic materials, the equations that govern momen-

ﬂuid). We consider that the ﬂuid (f-constituent) behaves as a New- 824

764 tum transfer in the cellular biological medium, on the B-scale of

tonian ﬂuid, and the solid (s-constituent) behaves as a linearly 825

765 observation, are [36]

elastic isotropic solid. For the systems under consideration, it is 826

766 Momentum balance in the cellular biological medium

767 reasonable to neglect the convective momentum transfer and mass 827

UN

769 r reff ¼ 0 ðA1Þ production–consumption (for time scales of observation much 828

smaller than the characteristic time of cell division). Under these 829

770 Constitutive equation for the ‘‘effective” stress tensor

771 h i assumptions, in the context of biphasic mixture theory, the equa- 830

T tions that govern momentum transfer in the cellular biological

773 reff ¼ leff ru þ ðruÞ þ keff eI aPI ðA2Þ 831

medium, on the B-scale of observation can be written as follows 832

774 Darcy’s ‘‘law” for the ﬂuid motion [50,53,55]: 833

775

Mass balance for the ath constituent ða ¼ f ; sÞ 834

keff

v¼ rP ðA3Þ

777 lf @ qa ua

þ r ðqa ua v a Þ ¼ 0 ðA12Þ 836

778 Mass balance for the ﬂuid @t

779

@h Momentum balance for the ath constituent ða ¼ f ; sÞ 837

781 ¼ r v ðA4Þ

@t @va X

782 Constitutive equation for the ‘‘variation in water content”

qa ua ¼ r ra þ Fx!a þ qa ua ba ðA13Þ

783

@t x–a 839

785 h ¼ ae þ P=M ðA5Þ

Constitutive equation for the stress tensor ra ða ¼ f ; sÞ 840

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h i

rs ¼ us PI þ ks ðr us ÞI þ ls rus þ ðrus ÞT ðA14Þ References 895

2 h i

[1] G.N. Bancroft, V.I. Sikavitsas, J. van den Dolder, T.L. Shefﬁeld, C.G. Ambrose, 896

842 rf ¼ uf PI lf ðr vf ÞI þ lf rv f þ ðrvf ÞT ðA15Þ J.A. Jansen, A.G. Mikos, Fluid ﬂow increases mineralized matrix deposition in 897

3

3D perfusion culture of marrow stromal osteoblasts in a dose-dependent 898

843 Constitutive equation for the interaction force F x!a manner, Proc. Natl. Acad. Sci. USA 99 (20) (2002) 12600. 899

[2] E.J. Bouwer, H.H.M. Rijnaarts, A.B. Cunningham, R. Gerlach, Bioﬁlms in porous 900

845 Ff!s ¼ Fs!f ¼ K ðv f v s Þ þ Prus ðA16Þ media, in: J.D. Bryers (Ed.), Bioﬁlms II: Process Analysis and Applications, 901

Willey-Liss, 2000, p. 123. 902

846 Saturation condition [3] T.G. Ellis, B. Eliosov, C.G. Schmit, K. Jahan, K.Y. Park, Activated sludge and 903

847 other aerobic suspended culture processes, Water Environ. Res. 74 (4) (2002) 904

849 uf þ us ¼ 1 ðA17Þ 385. 905

[4] G. Foley, A review of factors affecting ﬁlter cake properties in dead-end 906

850 Equation for the time evolution of volume fraction [54] microﬁltration of microbial suspensions, J. Membr. Sci. 274 (2006) 38. 907

[5] R.K. Jain, Delivery of molecular and cellular medicine to solid tumors, J. 908

F

852 us ¼ u0s þ u0s r us ðA18Þ Control. Release 53 (1998) 49. 909

[6] C.P. Ng, M.A. Swartz, Mechanisms of interstitial ﬂow-induced remodeling of 910

853 Relationship between velocity–displacement for the ath constituent ﬁbroblast-collagen cultures, Ann. Biomed. Eng. 34 (3) (2006) 446. 911

OO

[7] E.A. Swabb, J. Wei, P.M. Gullino, Diffusion and convection in normal and 912

854 ða ¼ f ; sÞ 913

855 neoplastic tissues, Cancer Res. 34 (1974) 2815.

[8] R.H. Bobo, D.W. Laske, A. Akbasak, P.F. Morrison, R.L. Dedrick, E.H. Oldﬁeld, 914

@ua

857 va ¼ ðA19Þ Convection-enhanced delivery of macromolecules in the brain, Proc. Natl. 915

@t Acad. Sci. USA 91 (6) (1994) 2076. 916

[9] X.-Y. Li, Y. Yuan, H.-W. Wang, Hydrodynamics of biological aggregates of 917

858 where ua is the volume fraction (the exponent ‘0’ denotes the initial different sludge ages: an insight into the mass transport mechanisms of 918

859 value), qa is the true density, v a is the velocity, ua is the displace- 919

PR

bioaggregates, Environ. Sci. Technol. 37 (2003) 292.

860 ment, ra is the ‘‘partial” stress tensor of the ath phase, P is the ﬂuid [10] R.C. Evans, T.M. Quinn, Solute convection in dynamically compressed 920

cartilage, J. Biomech. 39 (2006) 1048. 921

861 pressure, Fx!a is the interaction force (per unit volume) between [11] J.D. Fowler, C.R. Robertson, Metabolic behavior of immobilized aggregates of 922

862 the ath and xth constituents of the mixture, ba is a body force Escherichia coli under conditions of varying mechanical stress, Appl. Environ. 923

863 (e.g. in the case of gravity ba is set equal to the gravity acceleration Microbiol. 57 (1) (1991) 93. 924

[12] M.V. Hillsley, J.A. Frangos, Bone tissue engineering: the role of interstitial 925

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Please cite this article in press as: G.E. Kapellos et al., Theoretical modeling of ﬂuid ﬂow in cellular biological media: An overview, Math. Biosci. (2010),

doi:10.1016/j.mbs.2010.03.003

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