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Journal of Membrane Science 454 (2014) 359381

Contents lists available at ScienceDirect

Journal of Membrane Science


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

Review

Biomimetic membranes: A review


Yue-xiao Shen a, Patrick O. Saboe a, Ian T. Sines a, Mustafa Erbakan b, Manish Kumar a,n
a
Department of Chemical Engineering, The Pennsylvania State University, University Park, PA 16802, USA
b
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA

art ic l e i nf o a b s t r a c t

Article history: Biomimetic approaches to developing membranes for separations have seen a renewed interest in recent
Received 11 October 2013 years. Biomimetic membranes incorporate biological elements or borrow concepts, ideas or inspiration
Received in revised form from biological systems. Such membranes can take advantage of the strategies evolved by nature over
6 December 2013
billions of years for improving transport efciency and specicity. This review covers biological
Accepted 7 December 2013
paradigms that are relevant to membranes for separations and then presents an overview of strategies
Available online 17 December 2013
that are inspired by these paradigms. It also presents both fundamental and practical challenges to
Keywords: implementation of these strategies at application relevant scales.
Articial channels & 2013 Elsevier B.V. All rights reserved.
Block copolymers
Biomimetic membranes
Membrane proteins
Nanopores

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
2. Biological membrane separation paradigms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
2.1. Surface layer proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
2.2. The lipid bilayer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
2.3. Carrier mediated transport in biological membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
2.4. Membrane protein mediated separations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
2.5. Biological antifouling strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
3. Synthesis and application of biomimetic separation membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
3.1. Biomimetic sieves and nanopores. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
3.2. Biomimetic solution diffusion membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
3.3. Carrier mediated biomimetic membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
3.3.1. Liquid membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
3.3.2. Ion-selective ionophore-based membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
3.4. Channel mediated biomimetic membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
3.4.1. Lipid and block copolymer based biomimetic membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
3.4.2. Membrane protein based biomimetic membranes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
3.4.3. Articial channel based biomimetic membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
3.5. Bio-inspired antifouling separation membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373

Abbreviations: ABA or PMOXA-PDMS-PMOXA, poly-(2-methyloxazoline)-block-poly-(dimethylsiloxane)-block-poly-(2-methyloxazoline); AHL, acyl homoserine lactone;


AQP0, Aquaporin 0; AqpZ, Aquaporin Z; BCP, block copolymer; BLM, bulk liquid membrane; CNT, carbon nanotube; COP, 2-chloro-2-oxo-1,3,2-dioxaphospholane; DOPC,
1,2-dioleoyl-sn-glycero-3-phosphocholine; DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt); EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride; ELM, emulsion liquid membrane; FG-Nups, phenylalanineglycine nucleoporins; FO, forward osmosis; GAMA, D-gluconamidoethyl methacrylate; HL,
-hemolysin; Imp, importin-; ISE, ion selective electrode; LM, liquid membrane; LMH, L m  2 h  1; MOF, metal-organic framework; mPoPR, molar polymer to protein ratio;
NF, nanoltration; NMR, nuclear magnetic resonance; NPA, asparagineprolinealanine; NPC, nuclear pore complex; OmpF, outer membrane protein F; PANCHEMA, poly
(acrylonitrile-co-2-hydroxyethyl methacrylate); PB-PEO, poly(butadiene)-block-poly(ethylene oxide); PDMS, polydimethylsiloxane; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-
3-phosphocholine; POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1,-rac-glycerol); QS, quorum sensing; RO, reverse osmosis; SDS, sodium dodecyl sulfate; SEM,
scanning electron microscopy; S-layer, surface layer; SLM, supported liquid membrane; SUM, S-layer ultraltration membrane; TEM, transmission electron microscope
n
Corresponding author. Tel.: 1 814 865 7519.
E-mail address: manish.kumar@psu.edu (M. Kumar).

0376-7388/$ - see front matter & 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.memsci.2013.12.019
360 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

4. Challenges and opportunities for biomimetic membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375


4.1. Biomimetic nanopores. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
4.2. Carrier mediated biomimetic membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
4.3. Membrane protein mediated biomimetic membranes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
4.4. Articial channel based membranes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
4.5. Biomimetic antifouling strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
5. Outlook for biomimetic membranes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

1. Introduction
2. Biological membrane separation paradigms
Mankind has always been fascinated with biological systems [1]
due to their complexity and their efciency in completing tasks Biological membranes rely on their intricate structures and a
required for living organisms to thrive. In recent years there has been host of different mechanisms to implement efcient separations
a rapid increase in the understanding of molecular structure [2] and (summarized in Fig. 1 and Table 1). Thus they represent excellent
function of biological molecules (see single molecule studies on models that provide inspiration for synthetic membrane design.
biomolecules [36]). Concurrently, rapid advances in molecular The following sections discuss these paradigms in detail.
engineering through supramolecular chemistry [7] and sophisticated
high-resolution analytical techniques have increased our ability to 2.1. Surface layer proteins
mimic biological structures with near molecular precision. These
advances have also generated interest in the area of biomimetic Ordered arrays of proteins assembled on the exterior of cell
membranes. Cell membranes conduct substrate and solvent (water) walls of prokaryotic cells are known as surface layer (S-layer)
transport with exceptional selectivity and high transport rates that proteins [26]. These proteins are bound noncovalently to an
are unprecedented in synthetic systems. These efcient membranes underlying lipid bilayer, or cell surface bound polymer molecules
are also of interest because living organisms have evolved excellent such as peptidoglycans, teichoic acids and lipoglycans (Fig. 2(a)).
antifouling capabilities both at the cellular level and at higher levels S-layer proteins are arranged in oblique, square or hexagonal
of organization (e.g., lotus leaves [8] and shark scales [9]). arrays [26,27] and form porous membranes with sizes ranging
The increasing interest in biomimetic membranes across various from approximately 2 to 8 nm and porosities from 30% to 70%. S-
disciplines has resulted in the publication of several reviews addres- layer protein arrays have been imaged by high-resolution electron
sing various aspects of this eld. In particular, the reviews by Meier microscopy and scanning force microscopy (Fig. 2(b)) [28,29]. The
and coworkers have covered the area of block copolymer (BCP) S-layer provides functions such as cell protection, cell adhesion,
biomimetic membranes extensively [1014]. A recent book chapter surface recognition, molecular sieving, and molecule and ion traps.
review from our group traced the research on lipid and polymer In vitro self-assembly of S-layer proteins into regular lattices
identical to those observed in vivo has been demonstrated on
based membranes back to biological membranes [15]. Nielsen's
solid surfaces, at air/water interfaces, and in lipid vesicles [26].
contributions to a recent book [16] and another review [17] have
Because of their ideal isoporous structure, S-layer membranes
focused on the use of membrane proteins in BCP and lipid matrices
have been proposed for production of ultraltration membranes
to develop separation and sensor membranes. There have been other
with very sharp molecular weight cutoffs [30]. Schuster et al.
reviews on the methodology and application of solid supported lipid
synthesized S-layer ultraltration membranes (SUMs) by deposit-
and to a lesser extent polymer membranes as biomimetic mem-
ing S-layer fragments of Bacillus sphaericus CCM 2120 as a
branes [1822] and on their application to sensors [23]. Two
continuous layer on microltration membranes followed by che-
excellent reviews focused on the use of aquaporin-based biomimetic mical crosslinking (Fig. 2(c)) [31]. The high density and well-
membranes for desalination were published recently [24,25]. Despite dened position of carboxylic groups on the surface of SUMs can
the number of reviews listed above available on this topic, a be chemically modied to display different surface charge proper-
comprehensive overview of biomimetic approaches relevant to ties [32,33], and exploited for immobilization of bio-functional
membrane separations does not exist. This review presents for the macromolecules such as enzymes for biological surface mediated
rst time a broad thematic description of the principles that reactions [34]. Other applications of S-layer membranes include
biological membranes utilize for efcient separations while main- supported lipid membranes and nanoparticle assemblies [31,35].
taining selectivity and performance. It also describes current imple- Although S-layers provide a route for surface modications, as
mentations and promise of biomimetic approaches to developing well as ltration with antifouling properties [33,3638], they have
membrane materials and processes. not been used on larger scales perhaps due to scale up considera-
This review rst discusses biological membrane paradigms (struc- tions and membrane instabilities.
tures and mechanisms) that are relevant to separations from the
perspective of a single cell. It then describes hybrid-biological and 2.2. The lipid bilayer
synthetic biomimetic materials inspired by these biological paradigms
for efcient separations and operations including the use of lipid-like The lipid bilayer provides a dynamic but stable barrier between
polymers, membrane proteins and articial channels mimicking extracellular and intracellular compartments of a biological cell. The
membrane proteins. The subsequent sections cover the antifouling permeation of small uncharged molecules through a bilayer is
strategies inspired by cellular coatings, quorum sensing molecules described by the solution diffusion model where molecules must
released by cells and biological surface morphology. The review enter the membrane and diffuse through the hydrocarbon section
concludes with a detailed discussion on the fundamental and practical of the membrane in a two-step transport mechanism. This trans-
challenges and a future outlook section on the application of biomi- port is due to a chemical potential gradient [39] and the perme-
metic materials to larger scale separations processes. ability of the membrane is dened as PKD/d, where K is the solute
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 361

Cell releases antifouling chemical


signals to prevent biofouling.

S-layer proteins on the Glycocalyx oligosaccharide chains


surface of cell outer membrane on the outer cell membrane surface
show lattice structure. show antifouling properties.

The zwitterionic groups present


on the lipid head group provide
resistance to protein adhesion.
Outer membrane

Lipid bialyer allows


for passive diffusion.

Inner membrane

ATP
Membrane proteins facilitate Membrane proteins facilitate
active transport using ATP. passive transport.
Ionophores mediate transport across
lipid bilayer by complexing specific ions.

Lipid Membrane protein (channel) Ionophore

Glycocalyx Membrane protein (transporter) Antifouling signals

S-layer protein Membrane protein (pump) Solutes

Fig. 1. Biological membrane separation and antifouling strategies for an example of a gram-negative bacterial organism. These organisms perform size graded membrane
ltration, which is comparable to similar strategies used in membrane ltration. Structures on the outer membrane surface provide coarse ltration (surface layer proteins)
and fouling resistance. The second level of ltration is through large outer membrane channels for macromolecular separations and specialized inner (or plasma membrane)
membrane proteins for specic transport of solutes and water using pumps, channels, and transporters. The simple membrane bilayers allow for passive diffusion of water,
gases and specic solutes by solution diffusion as well as by carrier mediated diffusion of ionophores in the hydrophobic membrane interior. These cells also employ
antifouling strategies to prevent unwanted protein deposition on their surface and attachment by other microorganisms.

Table 1
Biological membrane separation paradigm.

Membrane type Dimensions or mechanism Location (in biological systems) Relevant membrane applications

Surface layer (S-layer)


28 nm of pore size External membrane surface Ultraltration membrane
membranes
enveloping the cell and cell Reverse osmosis and forward osmosis
Lipid bilayers Nonporous, diffusion
compartments membranes
Ionophore based membranes Nonporous, diffusion by carrier Hydrophobic region of lipid bilayers Electrode sensors, liquid membranes
Membrane protein facilitated Biomimetic desalination membranes, articial
0.31.5 nm of pore size Transmembrane
lipid bilayers channels
Surface physiochemical interactions, Membrane surfaces
Biological antifouling surface antifouling chemical signals, surface (blood cell membrane, plant and animal Surface antifouling coating for separations
topography skin)

Fig. 2. Surface layer (S-layer) membranes. (a) Illustration of bacterial cell membranes with S-layer proteins (hexagonal lattice). (b) Inverse fast Fourier transform image of re-
assembled B. sphaerius S-layer taken from the waterlipid interface. Reproduced with permission from Ref. [29]. Copyright 2008 Elsevier Ltd. (c) Electron micrograph of an
S-layer ultraltration membranes. Reproduced with permission from Ref. [31]. Copyright 2001 American Chemical Society.
362 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

partition coefcient between water and the hydrocarbon section of chloride detection by utilizing the chloride ionophore I (meso-
the bilayer, D is the solute diffusivity in the membrane, and d is the Tetraphenylporphyrin manganese (III)-chloride complex, Fig. 3(b)).
thickness of the hydrocarbon section. The linear relationship The ion-selective membrane in ISE is fabricated by evaporating the
between permeability and the solute partition coefcient is known solvent in the mixture of polymers (e.g., poly(vinyl chloride)),
as Overton's rule [40]. The solution diffusion type transport of small ionophores and other additives such as plasticizers. The chloride
molecules such as water, nutrients, and gas molecules across ISE has been successfully applied to measure chloride in blood
bilayers is an essential type of transport across biological mem- serum and intracellular environments [50]. Ionophores also have
branes such as the bloodbrain barrier [4144]. Ions can also be applications in liquid membranes (LM) due to their selectivity (see
transported through the lipid bilayer at a slow rate [45], although a Section 3.3.2) [51,52].
higher level of control is exerted by protein based channels, pumps
and transporters as described in a subsequent section. Osmotic
pressure across cell walls is balanced through water transport, 2.4. Membrane protein mediated separations
which can either expand or shrink the volume of a cell. Osmotic
and water permeation principles present at the cellular level Biological cells are highly efcient at transporting materials
have been relevant and in part guided the understanding and across their membranes due to the presence of specic membrane
design of membrane technologies for reverse osmosis (RO) and proteins facilitating both passive and active transport. These
forward osmosis (FO) desalination [46]. proteins can be grouped into three types based on their transport
mechanisms: channels, pumps and transporters (Fig. 4) [53].
2.3. Carrier mediated transport in biological membranes Channels are transmembrane passive pores. Their selectivity
depends on size, charge, and interaction of the substrates with the
The diffusion of molecules across biological membranes can be protein structure. The most common channels are gap junctions,
facilitated by carriers called ionophores residing in the hydrophobic porins, water channels, and ion channels [53]. The driving force for
core of the lipid membrane. These carriers were discovered through transport of solutes by channels is a concentration gradient across
their role in catalyzing energetic processes in the mitochondria of the membrane. The transport rate for channels is the highest of all
microorganisms by facilitating transport of ions such as Na , K , membrane proteins as minimal or no conformational change is
Ca2 , Mg2 and Cl  [47,48]. Ionophores are macrocyclic peptides required for transport. They are orders of magnitude faster than
that have oxygen atoms or other compatible ligands to provide a the next fastest membrane protein transporters, which require
binding pocket for a specic ion. When the ion is bound to the conformational changes over a larger time scale [53]. Transporters
ionophore, the ion's charge is delocalized to create a membrane can be grouped into three types based on their transport
soluble complex, which can diffuse across a bilayer with a max- mechanisms: uniporters, symporters, and antiporters. Uniporters
imum turnover rate on the order of thousands per second. The ux transport one solute down its concentration gradient; symporters
of ions is linearly proportional to the carrier concentration and is use the energy stored in the electrochemical gradient for one
driven by a concentration gradient and electrophoretic drift of the solute to move another solute upstream in the same direction,
ionophore. Equilibrium across the membrane is characterized by while antiporters use the gradient for one solute to move
both concentration and membrane potential according to the another solute up its gradient in the opposite direction. Pumps
Nernst equation and can be utilized to design ion selective electro- move ions or electrons against the concentration gradient using
des. A well-known ion selective electrode (ISE) is based on the K chemicals or light as energy sources. Like transporters, pumps
ionophorevalinomycin, which has a high afnity for potassium have binding sites for specic ions or substrates and may undergo
over other cations. The transport rate by a single valinomycin a conformational change. This change is driven by conversion of
molecule (referred to the association and dissociation constants of ATP to ADP, or by absorbing photons. The transport rate of pumps
potassium and valinomycin complex at the interface, the transloca- in general is the slowest of the three types of membrane pro-
tion constant of the complex across the membrane) is  104 K teins when considering ions (Fig. 4) [53]. Electrons are moved
ions s  1 [49]. A typical ISE is shown in Fig. 3(a). This ISE is used for most efciently by photosynthetic pumps, which utilize bound

Electronic conductor

N
C
l

Internal reference electrode N Mn N

N
Inner filling solution

Ion-selective membrane
Chloride ionophore I

Fig. 3. Ionophore based membranes: (a) schematic illustration of a traditional ion selective electrode. Ion-selective membranes are composed of specic polymers,
ionophores, and additives; (b) structure of the chloride ionophore I. The central manganese can strongly complex to chloride.
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 363

l
l l l l l l

l l l l l l
Fig. 4. Main membrane protein classes and their approximate transport rates. Channels provide passive transport across a bilayer and can be highly selective. Transporters
and pumps work through a bind, transport and release strategy; where specic external binding sites are rst occupied, allowing for transport across the protein, which is
dependent on the mechanism and structure of the protein.

l l l
l ll ll

l l
l l l

l l l l
l
l

ll
l l l
l

l
l
l
l

l l

Fig. 5. Reabsorption of critical solutes from the proximal convolute tubule of the nephron is via a series of membrane protein mediated transport steps. Blood is ultraltered
through Bowman's capsule and enters the proximal convoluted tube, which is surrounded by the tubular cells that are in turn surrounded by capillaries. The capillary color
turning from red to blue shows the transition from artery to vein. The glomerular ltrate contains high concentrations of salt, nutrients and other small molecules. Via a
combination of membrane proteins in the tubular cell (composed of Na /H antiporter, Na /K ATPase pump, Na /Cl  symporter, sodium glucose transporter 2, glucose
transporter 2, water channel aquaporin 1, p-aminohippurate/anion antiporter and other membrane proteins); Na , Cl  , HCO3  , water, glucose and amino acids are
reabsorbed by the tubular cells and reenter the capillary while wastes (such as acid, base and drug metabolites) are secreted into the lumen for excretion. (For interpretation
of the references to color in this gure legend, the reader is referred to the web version of this article.)

redox cofactors spaced for efcient electron transfer across the ultraltration membrane to retain large proteins. The glomerulus
protein [54]. ltrate in the proximal tubule lumen contains water, salts and other
Here we introduce two typical human organ systems, the small solutes. The proximal tubule is surrounded by tubular cells
kidney and the eye lens, as examples of membrane separation that are in turn surrounded by capillaries containing blood, in
systems where complex separations are achieved by a combina- which important components can be reabsorbed. A sophisticated
tion of different membrane proteins, which work together to membrane protein transport system in the tubular cells is respon-
maintain the function and homeostasis of these organs. sible for mediating the reabsorption of salts, water and nutrients
Kidneys are responsible for the regulation of electrolytes, pH, from the glomerular ltrate while excluding toxins and wastes (see
nutrients, toxins and wastes such as urea in the human body [55]. details in Fig. 5) [55,56].
The proximal tubule in the nephron plays a large role in this Another intricate membrane protein based transport system lies in
function (Fig. 5). The proximal tubule receives the blood ltrate the deceptively simple mammalian eye lens. The eye lens is an
from glomerulus through Bowman's capsule, which acts like an avascular tissue, not supplied by blood vessels in order to enhance
364 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

transparency. The eye lens has evolved multiple packing layers of These proteins have six lipid membrane spanning domains, forming a
transparent ber cells, from differentiating bers near the surface to narrow pore of around 2.3 and lined with hydrophobic amino-acid
mature ber cells in the center (Fig. 6) [5760]. On the surface, a single residues which results in single-le water transport at very high rates
layer of epithelial cells covers the lens from the anterior to the equator while excluding all other solutes including protons [64]. The unique
and supplies nutrients and water that are then transported into the selectivity mechanisms of aquaporins include (1) size exclusion of the
ber cell layers through a network of membrane proteins. The narrowest part of the pore that rejects most hydrated ions larger than
overabundance of crystalline patches of membrane proteins (e.g., the pore size; (2) electrostatic repulsion by the charged arginine
gap junction channels [61] and aquaporin 0 (AQP0) [62]) in lens ber residue close to the selectivity lter region that rejects positively
cells not only provides mechanical support and light transmission charged ions and (3) water dipole reorientation (proton exclusion) that
properties, but also allows the transport of nutrients and wastes that facilitates a single le transport of water molecules (Fig. 7(a)). The fast
maintains the cell homeostasis. transport of water in aquaporin channels can be explained by an
We further discuss two major membrane proteins mentioned in analogy to frictionless ow (slip ow) in smooth narrow hydro-
the two organ systems discussed above: aquaporins and Na /K phobic channels such as carbon nanotubes instead of conventional
ATPases. Aquaporins are water channels and are a family of membrane Poiseuille ow [65]. Na /K ATPases belongs to P-Type pump
proteins that specically transport water across cell membranes [63]. category where ATP binding and dephosphorylation are used to drive

Fig. 6. Structure and function of mammalian eye lens. (Left) The architecture shows the monolayer epithelial cells cover ber cells from the equator to the anterior; eye lens
is composed of multiple layers of transparent ber cells, evolving from differentiating bers (dark blue) near the surface to mature ber cells (light blue) in the center. The
gray arrows display the ow circulation in the eye lens. (Right) A segment of eye lens at the equator shows microcirculation mediated via a group of membrane proteins. The
membrane proteins within the surface layer power the circulation of nutrients and water while the proteins inside the lens ber provide mechanical support, translucency
and interior permeability. Reproduced with permission from Ref. [58]. Copyright 2001 American Physiological Society. (For interpretation of the references to color in this
gure legend, the reader is referred to the web version of this article.)

l
l
l

Fig. 7. Aquaporins and Na /K ATPases: (a) Mechanisms for rejection of solutes illustrated using aquaporin 1 as a model. Histidine 180 (His 180) and Arginine 185 (Arg 185)
form the narrowest part of the channel (2.8 ) that excludes all other larger solutes except water molecules. Arg 185 is also positively charged that rejects positively charged
solutes by electrostatic repulsion. Arg 185 and two conserved asparagineprolinealanine (NPA) motifs form a series of hydrogen bonds reorienting the water molecules the
water and preventing passage of protons. (b) Na /K ATPase is composed of a transmembrane domain, an actuator domain (A domain), a phosphorylation domain (P
domain), a nucleotide-binding domain (N domain) and other subunits. Upon ATP binding and phosphorylation of P domain, there is a conformation change of the protein
leading to the transport of Na and K though transmembrane domain across the cell membrane.
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 365

transport. P-Type pumps usually contain four subunits: the transmem- to regulate the formation, maturation and dispersion of biolms.
brane domain residing in the membrane, actuator domain (A domain), The best characterized QS system is acyl homoserine lactone
phosphorylation domain (P domain) and nucleotide-binding domain (AHL)-mediated QS of Gram-negative bacteria [80,81]. AHLs are
(N domain) (Fig. 7(b)) [66]. The P domain has an ATP-binding site and synthesized and secreted out of cells. When the extracellular AHLs
the transmembrane domain has regulatory functions. Binding of Na reach a certain concentration, they reenter the cells via either
and K to be transported onto the specic binding sites leads to an active or passive transport and bind to a cytoplasmic receptor. The
increase in ATP binding afnity. Upon ATP binding and phosphoryla- formed active dimers bind to the specic regions of genetic
tion of P domain, there is a conformation change of the protein so that promoter sequences and activate gene expression responsible for
3 Na are released to the other side of the membrane by exchanging biolm formation and other processes. Organisms control or
2 K . The efcient transport properties of natural membrane proteins prevent the growth of alien biolm formation by interrupting
are being utilized to develop articial channels and novel materials for the AHL-mediated QS cycle. Extracted chemicals from these
separation [6769]. organisms display inhibition of QS signals or interference with
QS receptors [82,83]. It is worthwhile to mention that for some
organisms, this QS regulation is reversed. For example, Vibrio
2.5. Biological antifouling strategies cholerae [84] and Rhodobacter sp. [85] form biolm when AHL
concentration is low and the biolm is dispersed when AHL
Biological surfaces show excellent antifouling properties towards reaches high concentrations. These results provide a basis for
common foulants ranging from small proteins to whole cells. Anti- developing a bio-inspired approach for antifouling applications in
fouling mechanisms seen in biology use a combination of the membrane separation technologies [86,87]. Porcine kidney acylase
following approaches: (1) surface physiochemical interactions: the I, which can inactivate the AHL molecule by amide bond cleavage,
afnity between foulants (e.g., proteins) and surfaces depends on a was conrmed to mitigate biofouling in membrane bioreactors
combination of steric effects, electrostatics and hydrophobic interac- [88]. D-tyrosine was found to be capable of preventing irreversible
tions, which are specically tuned at the cell membrane surface to biofouling of P. aeruginosa in a bench scale nanoltration (NF)
prevent fouling; (2) antifouling chemicals: these are released to system [89]. Other biological anti-biofouling paradigms include
prevent adhesion by other cells; (3) nano and microscale topography: nitric oxide-induced biolm dispersal [90], disruption of biolm
this inuences uid dynamics near the surface and minimizes chances by bacteriophage [91] and enzymatic disruption [92]. One caveat is
for contact and thus attachment between biological surfaces and that these biological anti-biofouling procedures have mostly been
foreign cells (Fig. 8). applied to laboratory pure cultures [87].
Many biological cells have specic functional groups on the outer Surface topography is crucial to the attachment of cells onto
layer of cell membranes that prevent exterior foulants from adhesion surfaces. Biofouling can be caused by bacteria ( 41 m), algal
(zwitterionic lipid head groups in Fig. 1). Protein adsorption and spores (510 m) and even larger cells. A common attachment
adhesion onto the red blood cell surface are inhibited by the theory is that if microtexture dimension is larger than foreign cells,
zwitterionic phosphocholine layer on the cell surface [71]. Both more attachment area is exposed so that the fouling is increased.
positive and negative charged units of zwitterionic materials induce In contrast, cells that are much larger than the microtexture
electrostatic hydration (ionic solvation) so that a signicant amount wavelength generally are less likely to attach onto the surface
of water molecules are strongly and stably bound to the zwitterions [93]. Shark skin has a longitudinal rib pattern in terms of micro-
which reduces protein adsorption [72,73]. This hydration lm has topography and show excellent antifouling properties against
inspired the development of zwitterionic polymer coatings for ectoparasites [82,83]. SharkletTM technology, characterized with
antifouling applications [7476]. In a similar mechanism, superhy- its shark-mimicking microscopic texture that impedes the growth
drophilic surfaces can be coated with a thin water layer, analogous to of bacteria and algae, is manufactured for antifouling application
sh scales, preventing foulant attachment. In another strategy, the in hospitals against bacterial infections and in marine coatings
glycocalyx of cell membranes (also highlighted in Fig. 1) contributes against potential spread of marine organisms [94].
to prevent undesirable non-specic protein adhesion via a combina-
tion of electrostatic and entropic forces (termed as steric stabiliza-
tion) [77]. Oligosaccharide grafted polymers have been successfully 3. Synthesis and application of biomimetic separation
developed to mimic glycocalyx-like antifouling surfaces [78,79]. membranes
Anti-biofouling effects can be achieved by interrupting cell
adhesion and biolm formation. One effect is through interfering The following section describes biomimetic membrane synth-
with bacterial quorum sensing (QS). Bacterial communities use QS esis and strategies corresponding to the materials and methods

Surface grafted polymer Immobilized or free antifouling Modified topography deters


brushes prevent exterior signal chemicals prevent the attachment of cells.
foulants from adhesion. biofilm growing on the surface. Grafted polymer brush

Antifouling signal chemicals

20 m Foulants
Top view
Surface microtexture

Membrane
Fig. 8. Biological antifouling strategies at interfaces can be divided into three major categories based on the antifouling mechanisms: (a) Surface physiochemical interactions;
(b) antifouling signal chemicals; (c) nano and microscale topography. The inset shows the scanning electron microscopy image of the surface structures on the lotus leaf with
self-cleaning properties. Reproduced with permission from Ref. [70]. Copyright 1997 Springer-Verlag.
366 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

Membrane proteins incorporated Nanopore membranes modified with Artifiical channels incorporated
into lipid or block copolymer bilayers functional molecules within the pores into block copolymer bilayers

Membrane proteins incorporated Membranes modified with functional Artifiical channels incorporated
into nanopore membranes molecules on the surfaces into lipid bilayers

Fig. 9. Three approaches to biomimetic membranes for separations: (a) biomimetic-hybrid membranes; (b) biomimetic-modied membranes; (c) biomimetic-synthetic
membranes.

Ion beam
TEM
electron beam glass

Etch Pt
Si
Chemical ecthing
Pt
SiO2

Fig. 10. Fabrication of nanopore membranes: (a) porous structures produced in polymer lm using ion track-etching technology; (b) fabrication of silicon oxide nano-sized
pores using electron beam drilling. Reproduced with permission from Ref. [97]. Copyright 2003 Nature Publishing Group. (c) Fabrication of nanopore using nanopipettes.
Reproduced with permission from Ref. [98]. Copyright 2004 American Chemical Society.

used by biological membranes (here the synthesis and strategies beam sculpting (i-beam lithography), electron beam drilling
in subsection numbers correspond to the materials and strategies (e-beam lithography) and nanopipette etching. Track-etching
in the biological membrane section (Section 2)). Research in this technology rst utilizes heavy ions to produce a localized damaged
area can be divided into three biomimetic approaches (summar- hole, termed as latent track, in substrates such as polycarbonate,
ized in Fig. 9): (1) biomimetic-hybrid membranes, incorporating polypropylene, and polyvinyl uoride membranes (Fig. 10(a)) [95].
biological membrane proteins and carriers reconstituted into The irradiation current density of the heavy ions controls the
natural or synthetic supporting membranes; (2) biomimetic- number of tracks. The resultant latent tracks are further converted
modied membranes, made from synthetic materials and mod- into pores by chemical etching, which is also a critical step in
ied with functional molecules so that it is smart and able to controlling pore size and shape. It is possible to achieve a variety of
mimic the function of natural membrane proteins; (3) biomimetic- pore geometries by manipulating etch rates by varying type and
synthetic membranes, incorporating articial channels into synthetic concentration of the etchant, reaction time and duration of etching
materials. The following subsections provide detailed descriptions on process. A similar approach to ion track-etching is ion beam
these membranes. sculpting, which uses feedback from ion-detectors below the
substrate to monitor pore size [96]. The focused beam rst erodes
3.1. Biomimetic sieves and nanopores the substrate and opens a pore, which can be narrowed and even
closed due to the surface diffusion, viscous ow and redisposition
Biomimetic sieves and nanopores can be classied into two under diffuse beam condition. Electron beam drilling is typically
groups. One is biological pores directly embedded into synthetic performed using a transmission electron microscope (TEM), grant-
materials, including engineered -hemolysin (HL) and outer ing immediate visual feedback on pore formation (Fig. 10(b)) [97].
membrane proteins. These hybrid systems will be discussed in a By utilizing TEM, it is also possible to modify the pore geometry by
later section Channel mediated biomimetic membranes. The other adjusting the electron beam, permitting pore modication. Fabri-
approach is the utilization of functional molecules to modify syn- cation of nanopores using nanopipettes was developed by White
thetic organic/inorganic nanopores to manipulate specic trans- and coworkers (Fig. 10(c)) [98]. A sharp Pt wire is sealed into a
port. This type of biomimetic nanopores may have an advantage of glass capillary, and polished until the Pt disk of nanometer
mechanical and chemical stability over hybrid biological pore dimensions is exposed and used to create a truncated cone-
based membranes. shaped nanopore in glass via electrochemical etching. The pore
The rst step in preparing biomimetic nanopore membranes is geometry is dened by the Pt disk electrode.
fabrication of different shapes and structures of the nanopore After fabrication of the nanopores, chemical modication with
substrates (Fig. 10). Nanoporous materials can be produced using functional molecules is necessary to make a selective mem-
various fabrication technologies, such as ion track-etching, ion brane [99101]. Functional molecules can alter the charge and
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 367

R
Si
R
H2N R OO O
R Si
+ C2H5 C2H5 HS R R
O OH O NH + C2H5 OO O
OH Au S
EDC C2H5OH

Fig. 11. Three major approaches to chemical modication with functional molecules within synthetic nanochannel wall: (a) formation of peptide bonds between carboxyl
and amino groups using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC); (b) formation of covalent SiOSi bond between the alkoxy groups on the
saline and hydroxyl groups on the surface; (c) Formation of covalent SAu bonds between gold and thiol.

l
l
l l

l l

l
l
l
Fig. 12. Biomimetic nanopore membranes: (a) A nanopore membrane (gray) is coated with a polymer lm (green) using Sn2 ions (yellow) to promote chemical adsorption.
Separation of molecules in solution can be carried out on the basis of specic interactions with the polymer coating. Reproduced with permission from Ref. [104]. Copyright
2008 Nature Publishing Group; (b) pH responsive nanopores via grafting zwitterionic brushes. Reproduced with permission from Ref. [105]. Copyright 2009 American
Chemical Society; (c) the biomimetic nuclear pore complex (NPC, inset shows the original NPC structure. Reproduced with permission from Ref. [107]. Copyright 2010 Cold
Spring Harbor Laboratory Press.) is engineered by attaching phenylalanineglycine nucleoporins (FG-Nups) to a solid-state nanopore and the transport of Imp is measured
by monitoring the trans-pore current. Reproduced with permission from Ref. [109]. Copyright 2011 Nature Publishing Group. (For interpretation of the references to color in
this gure legend, the reader is referred to the web version of this article.)

hydrophobicity of the channel walls, control the pore size, provide nanopore membranes with functional polymers (Fig. 12(a)) [104].
recognition sites for a specic molecule, and make the pore both They utilized the coordination between Sn2 ions with the
chemically and biologically responsive [99]. Here we summarize the nitrogen and carbonyl groups from the track-etched polycarbonate
three most common approaches (Fig. 11). A common approach is membranes to add subsequent anionic coating layers. By control-
forming amide bonds between carboxyl and amino groups using a ling the coating layer properties, the modied membranes were
crosslinking reagent such as 1-ethyl-3-(3-dimethylaminopropyl)car- capable of discriminating small molecules based on size, charge
bodiimide hydrochloride (EDC), if the original pores have carboxyl or and hydrophobicity. Brushes can be dynamically responsive to
amine groups (Fig. 11(a)). Silicon oxide or alumina based membranes external stimulus, such as pH, temperature and ions [100]. For
can be modied using silanization chemistry because their hydroxyl example, nanopores modied with zwitterionic polymer brushes
groups displace the alkoxy groups on the silane thus forming a will display an overall positive charge and anion-selectivity at low
covalent SiOSi bond (Fig. 11(b)). Another major approach is pH, while transitioning to an overall negative charge and cation-
through thiol chemistry. A very thin gold layer is coated along the selectivity at high pH (Fig. 12(b)) [105]. The grafted layers can also
pore walls via electroless deposition, followed by the covalent binding be biomolecules in order to achieve desired afnities to specic
between gold and thiol, due to the spontaneous formation of SAu molecules. The nuclear pore complex (NPC) located within the
bonds (Fig. 11(c)) [102]. Thiol molecules can be further modied in cell's nuclear envelope is a highly selective, bidirectional trans-
order to achieve desired functional terminal groups. porter for a tremendous range of cargoes while preventing the
Biomimetic nanopore membranes can be functionalized to passage of nonspecic macromolecules (Fig. 12(c), inset) [106,107].
have a specic combination of specic size, shape, charge, hydro- Phenylalanineglycine nucleoporins (FG-Nups) polypeptides,
phobicity and afnity. These parameters can interact in a syner- which are believed to be the key component of the NPC's
gistic way to enhance the transport of certain molecules. Without selectivity mechanism, were tethered into nanopores to mimic
any modication, the bare nanopores can be used to reject natural NPCs (Fig. 12(c)) [108,109]. FG-Nups formed a dense
molecules by size discrimination. Siwy and coworkers synthesized barrier near the pore entrance, provided reversible binding to
track-etched SiN membranes, which acted as molecular sieves the receptor (e.g., Imp) and implemented its fast transport; while
differentiating smaller bovine serum albumin over larger immu- non-specic protein transport was strongly inhibited.
noglobulin G [103]. When two molecules are of similar size but
have different charges, molecules can be separated based on 3.2. Biomimetic solution diffusion membranes
electrostatic interactions. The aforementioned SiN membranes
selectively transported positively charged rhodamine and rejected The principles of solution diffusion are applicable to non-
negatively charged Alexa uorophore due to its negatively charged porous membrane technologies such as RO, FO and NF, but since
surface [103]. The pore size can be also precisely controlled via these technologies are not commonly considered biomimetic; they
attached polymers. Savariar et al. developed a strategy for coating are not included in this review (see the following references for a
368 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

review on current applications and state of the art of research on 3.3.2. Ion-selective ionophore-based membranes
these technologies [110115]). Another application of solution Ion-selective membranes utilize ionophores and are directly
diffusion membranes is liquid membranes. These membranes are analogous to the ionophores in biological bilayer processes (Section
often coupled with carriers to enhance the transport and we 2.3). Ion-selective membranes are composed of ionophores dissolved
introduce them below. in polymeric membranes (e.g., poly(vinyl) chloride, polyimide, sili-
cone rubber, polyurethane, acrylate, peruoropolymers). These poly-
mer materials provide an appropriate homogenous hydrophobic
3.3. Carrier mediated biomimetic membranes medium with superior thermal and mechanical stability, allowing
for ionophore complexes to freely move [128]. The major drawback
3.3.1. Liquid membranes of polymer matrices is their low uidity, which reduces the mobility
Liquid membrane (LM) systems facilitate liquid-liquid extraction of ionophores. Addition of plasticizers, which are fully miscible with
and membrane separation simultaneously. It is analogous to solution the polymer, lower the glass transition temperature of the polymer
diffusion process in lipid bilayer of biological membranes, but this and helps the membrane retain uidity. In addition to plasticizers,
technology is not generally considered biomimetic [116]. It utilizes an anionic binding sites are used as additives to increase the ion
extraction solution to mediate transport from the source to the concentration in the membrane phase and lower membrane resis-
receiving phases due to a chemical potential gradient. The extraction tance to transport [52]. Ionophore-doped membranes have been
phase is often immiscible with the feed and stripping phases. Based on commercially applied in ion-selective electrodes but are still conned
their congurations, LM systems can be classied into three groups: to being sensing membranes rather than separation membranes
(1) bulk liquid membranes (BLM); (2) supported liquid membranes because of their ion ux limitations.
(SLM) and (3) emulsion liquid membranes (ELM). BLMs consist of two
aqueous feed and stripping phases isolated by a bulk organic, water- 3.4. Channel mediated biomimetic membranes
immiscible liquid phase. LM immobilized into a thin solid microporous
support is dened as SLM. In ELM systems, receiving phase is 3.4.1. Lipid and block copolymer based biomimetic membranes
emulsied and encapsulated in an immiscible liquid membrane made Biological membranes have exceptional selectivity and permeabil-
of amphipathic surfactant molecules and the emulsion is dispersed ity in terms of solute or water transport as described in Section 2.4.
into the feed solution (Fig. 13, left). The efciency and selectivity of The lipid bilayer is the primary component in biological membranes
transport in LM systems can be remarkably enhanced by the presence and provides a supporting matrix for incorporation of membrane
of carriers. Therefore, LM systems are often employed as carrier proteins. Since lipid bilayers are relatively unstable membranes
mediated separation systems. For heavy alkali metal cation, ligands compared to commercially available membranes, synthetic bilayers
such as crown ethers are often used as carriers [48], because they may be required in order to successfully mimic biological membranes.
provide multidentate chelating groups to bind the cation while the Amphiphilic BCPs have been shown to assemble into bilayer-like
hydrophobic shield assists in fast transport in the oil phase. Due to the structures [129,130]. They are most commonly synthesized for
simple process with small footprint, LM systems have been used to biomimetic applications as either diblocks with a hydrophilic and a
separate contaminants or recover useful chemicals such as heavy hydrophobic block, or as triblock copolymers with two hydrophilic
metals [117119], weak acids/bases [120,121], inorganic species [122] blocks and one hydrophobic middle block. There are several advan-
and hydrocarbons [123]. An illustration of ELM process is shown in tages of BCPs over lipid membranes including high mechanical and
Fig. 13. LM is a promising technology but still limited to small-scale chemical stability [129,131,132], low water and gas permeability [133]
commercial application because of the leakage and stability of LMs and customizable properties (e.g., a larger ranges of membrane
[51,124126]. Parameters such as LM composition, the selectivity and thickness [129] and end groups [134,135]).
concentration of carrier, pH, ion strength, operational temperature, Based on the fabrication procedures and congurations, articial
contact time, etc. are crucial to the performance of LM process [51]. bilayer membranes can be classied into two major types: bilayer
Detailed descriptions and solutions can be found in the specic review membranes and supported bilayer membranes. Bilayer membranes
papers and books [51,119,126,127]. are made to span an aperture. Lipids or BCPs are rst dissolved in

Internal aqueous phase Surfactant recovery


Hydrophilic head

Hydrophobic tail

Surfactant Carrier Pollutant

Regenerated
Aqueous Feed emulsion

Internal Emulsification
reagent
Internal
reagent

Internal Extract
reagent
Demulsification

Internal Reactor
reagent

Liquid membrane (oil layer) Raffinate

Emulsion globule Settling

Fig. 13. Illustration of a typical emulsion liquid membrane (ELM) separation process: (1) emulsication of the liquid membrane and internal phase; (2) emulsion globule
contacting with feed phase; (3) settling the emulsion from the external feed phases after extraction; (4) demulsication and recovering both the pollutant chemicals and the
membrane phase. The left gure shows the overall concept of ELM system.
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 369

Substrate
Air Lipid
Monolayer

Liquid

Chemical crosslink

Porous substrate

Fig. 14. Strategies for making lipid and block copolymer based biomimetic membranes: (a) liposome or polymersome rupture approaches onto a solid substrate followed by
chemical crosslinking; (b) LangmuirBlodgett transfer strategy: monolayer lms are rst created by adding solvent-solubilized lipids or block copolymers onto the airwater
interface. The monolayer is then transferred and compressed onto a moving vertical substrate. The second layer can be transferred during the subsequent lowering step.

appropriate organic solvent and then applied to small Teon separation technologies, critical questions still remain including Are
apertures to form a freely supported membrane upon solvent aquaporins stable enough to withstand the conditions that may exist
evaporation and hydration (occurring on opposite sides of the during separation (e.g., high salinity, pressure, fouling and the pre-
membrane interface). Two commonly used assembly approaches sence of microbes)? and How to produce large-area and defect free
are the painting method [136] and the folding method [137]. membranes? Considering the above questions, aquaporin studies
Membrane proteins can be incorporated into the membrane have been mostly limited to small scales (e.g., lipid or polymer vesicles
through direct addition of detergent solubilized proteins or proteo- of sizes  100200 nm). Sun et al. used nickel-chelating lipids as one
liposomes to the membrane adjacent aqueous phase. Although component of lipid mixture and incorporated AqpZ into planar lipid
bilayer lipid membranes are generally unstable and have a life span bilayers via LangmuirBlodgett transfer; however no water perme-
on the order of hours, they have provided a platform for studying ability or salt rejection test was conducted based on this fabrication
the properties of membrane proteins including HL, outer membrane method [144]. Most strategies rely on depositing functional aquaporin
protein F (OmpF), and aquaporins among others [17,138140]. vesicles onto porous substrates functioning as supports (Fig. 14(a);
Supported bilayer membranes are formed or deposited on a these studies are summarized in Table 2). Several strategies have been
solid substrate. The two main assembly methods used are vesicle studied to enhance deposition and immobilization of vesicles on the
deposition [22] and monolayer transfer [141]. In vesicle deposition support including direct deposition of vesicle onto the substrates,
(Fig. 14(a)), lipid or BCP vesicles are fused or ruptured onto the pressure assisted vesicle fusion [146,147,149,152,153], charge induced
substrates by hydraulic pressure, electrostatic interaction or chemical vesicle adsorption [146,150,151], magnetic enhanced vesicle deposi-
crosslinking. A commonly used monolayer transfer technique, Lang- tion [151], and chemical crosslinking between functionalized lipid/
muirBlodgett, has also been used to transfer lms formed at air polymer and the substrate [145,147,149,152154].
water interface onto solid supports (Fig. 14(b)) [141]. Supported While aquaporins are of interest in water ltration membranes,
bilayer membranes have recently been widely used to synthesize -hemolysin (HL) is a membrane protein being used for sensing
biohybrid ltration membranes. Water channel membrane proteins, applications and DNA sequencing. This protein, HL, is found in
aquaporins, have been reconstituted into lipid or BCP vesicles and the human pathogen Staphylococcus aureus bacterium, and is a
immobilized onto porous substratesthe studies in this eld will be mushroom-like transmembrane pore with a narrow constriction site
reviewed in detail in the following sections. of 1.4 nm. Due to its unique internal structure, HL can transport a
single strand of DNA while excluding double stranded DNA [101,156].
In addition, modied HL can be employed to detect other molecules
3.4.2. Membrane protein based biomimetic membranes such as proteins, metal ions, and drug molecules [101]. Dekker and
Membrane protein based biomimetic membranes can be coworkers rst made hybrid functional membrane via direct inser-
dened as biomimetic-hybrid membranes. In this type of mem- tion of HL into SiN nanoporous membranes (Fig. 15, inset) [157].
branes, natural membrane proteins are reconstituted into articial Another recent study showed that HL was capable of being
lipid bilayers, BCP bilayers or solid-state nanopores. These studies reconstituted into solid-supported poly(butadiene)-block-poly(ethy-
have increased exponentially in recent years. lene oxide) (PB-PEO) diblock copolymer membranes via monolayer
Water channel membrane proteins, aquaporins, are being studied transfer [158]. Similarly, another biological ion channel, Gramicidin-
and incorporated into water purication membranes due to their A, has been inserted into track-etched polycarbonate nanopores with
high water transport rate and selectivity properties. Providing a proof a signicant increase of ion diffusion coefcient through the mem-
of concept for aquaporin based-synthetic membranes, Kumar et al. brane [159]. In addition to protein pores, DNA origami (as articial
showed that the bacterial aquaporin, Aquaporin Z (AqpZ), remains channels, detailed information in Section 3.4.3.1) can be incorporated
active in BCP vesicles [133]. This hybrid systems is estimated to have into the SiN chip containing a nanopore to detect -DNA molecules
a water permeability up to 2 orders of magnitude higher than (Fig. 15) [160]. The SiN chip containing a nanopore was rst sealed
the existing desalination membranes and a selectivity approaching into polydimethylsiloxane microuidic channels. The origami chan-
100% [133]. Studies on aquaporin based desalination membranes nel tip was tagged with a double strand DNA in order to guide the
have rapidly increased in number over the last 2 years [142155]. voltage-driven self-assembly. The inserted channel blocking the pore
While aquaporins provide excellent material for the next-generation resulted in a lower and stable conductance level.
370 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

Table 2
Aquaporin liposome/polymersome based biomimetic membranes for desalination.

Vesicle Substrate Fabrication approach Permeability NaCl Note Reference


rejection

AqpZ-ABA Gold coated porous silicon Crosslink between disulde 8 LMH/bar 45% [145]
wafer functionalized ABA and gold.

AqpZ-DOPC NF-270, coated with Pressure assisted adsorption;  3.5 LMH/bar 20% [146]
DOTAP charge induced vesicle
adsorption.

AqpZ-ABA Track-etched membrane Hydraulic fusion; UV crosslink 16 LMH 98.8% FO mode; 0.3 M sucrose [147]
coated with gold between methacrylate of ABA as draw solution.
and acrylate on the substrate.

AqpZ-DOPC Polysulfone substrate Vesicles were embedded in the 4 LMH/bar 98% The fabrication used strong [148]
composite polyamide lm via detergent (SDS) and organic
interfacial polymerization solvent (n-hexane).

AqpZ-ABA Salinized cellulose acetate UV crosslink after vacuum 34 LMH/bar 33% [149]
fusion.

AqpZ-POPC/POPG/ Polyacrylonitrile substrate Charge induced vesicle 6 LMH/bar 95% MgCl2 as feed [150]
Cholesterol adsorption

AqpZ-POPC/POPG/ Polyacrylonitrile substrate Charge induced vesicle 15  20 LMH FO mode; 0.3 M sucrose [151]
Cholesterol adsorption; as draw solution and MgCl2
magnetic enhanced vesicle as feed
deposition

AqpZ-DOPC Polyacrylonitrile substrate Pressure assisted adsorption; 3.8 LMH/bar 65% [152]
crosslink between amine
functionalized lipid and the
surface polydopamine layer

AqpZ-ABA Track-etched membrane Hydraulic fusion; UV crosslink 17.6 LMH 91.2% FO mode; 0.3 M sucrose [153]
coated with gold between methacrylate of ABA as draw solution
and acrylate on the substrate

AqpZ-ABA Amine functionalized Chemical crosslink NF: 23 LMH/bar; NF:  39%; Using organic solvent [154]
cellulose acetate FO: 5.5 LMH FO:  50% and strong detergent
such as SDS
ABA-DOPC Poly(amide-imide) Encapsulated in the selective 36.6 LMH/bar 95% MgCl2 as feed [155]
substrate ayer of the membrane by
chemical crosslink

AqpZ: aquaporin Z; ABA: poly-(2-methyloxazoline)-block-poly-(dimethylsiloxane)-block-poly-(2-methyloxazoline) (PMOXA-PDMS-PMOXA); DOPC: 1,2-dioleoyl-sn-glycero-


3-phosphocholine; DOTAP: 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt); POPC: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; POPG: 1-palmitoyl-2-
oleoyl-sn-glycero-3-phospho-(1,-rac-glycerol); SDS: sodium dodecyl sulfate.

DNA DNA origami


chain tagged
-hemolysin

Nanopore
membrane
Current (nA)

Time (s)
Fig. 15. Schematic illustration of the insertion of a DNA origami into a SiN chip containing a nanopore (inset shows the insertion of -hemolysin with a 3 kbp double strand DNA
attached into a SiN nanopore [157]). The origami channel tagged with a double strand DNA was electrophoretically translocated through and inserted into a nanopore. The inserted
channel blocking the pore resulted in a lower and stable conductance level. Reproduced with permission from Ref. [149]. Copyright 2011 American Chemical Society.

These hybrid biomimetic membranes have the advantage of solid-state nanopore membrane [101]. However, other parameters
combining the precise structure of a biological pore with the robust- such as the functional reproducibility of biological proteins in the
ness, durability and the ability to control pore size and shape of a synthetic nanopores and the cost for fabricating these synthetic
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 371

nanopores are still challenging in this eld [161]. This hybrid approach chirality into cylindrical structures (Fig. 16 (b)) [174]. This channel
may turn out to be a powerful technique for biomolecule ltration and was designed to achieve controllable lengths to match the bilayer
sensing. thickness and have the ability to be functionalized on both external
and internal barrel surfaces. -Stacks are another structural motifs
3.4.3. Articial channel based biomimetic membranes that can serve as synthetic ion channels. An excellent example of -
Biological cell membranes conduct efcient and selective trans- stacks is the G-quadruplex ion channel (Fig. 16(c)) [175]. A single
port of solutes and water through sophisticated channel proteins. cyclic tetramer is rst formed by guanosine derivatives around
These proteins have inspired powerful synthetic approaches that potassium cation templates. The tubular structure comprising
have opened the door to a library of articial channels. Some of the G-quadruplex ion channel was formed due to the interaction
channels are designed directly from biological structures; others between each cyclic tetramer with several other cyclic tetramers
might be based on chemical synthesis and supramolecular assembly. stacking on top of each other. This channel acts as Na transporter
In a broad sense we dene biomimetic channels as follows: (1) The in the phospholipid bilayer. Metal-organic frameworks (MOFs) are
channel is designed to have a membrane-spanning tubular structure widely proposed as materials that can store gas due to its highly
with a thickness on the order of nanometers. (2) The structure has an porous structure [176]. A synthetic ion channel made of a well-
outer surface that interacts favorably with the membrane environ- dened MOF (copperpolyhedra framework) has been shown to be
ment. (3) The internal structure has been designed to accommodate capable of transporting proton and alkali-metal ions across lipid
the desired solute and provide a carefully tuned afnity to provide membranes [177]. Tecilla and coworkers provided another
selectivity. Most functional studies on articial channels are con- excellent MOF example (Fig. 16(d)) [178]. They used 10-,
ducted with vesicles or planar bilayer membranes. For ion or solute 20-mesodipyridylporphyrin to coordinate with Re (I) fragment,
channels, a pH or ion sensitive uorescent dye encapsulated in lipid forming thermodynamically stable porphyrin tetramers with a
or polymer vesicles can be used to track the intravesicular concen- 2 nm pore size. Functionalizing the carboxylic acid residues from
tration of the relevant species and determine the transport para- two Re (I)-porphyrin frameworks led to the hydrogen-bonding
meters [162]. 23Na NMR spectroscopy and ion selective electrodes driven dimerization of these two tetramers. The dimer formed
can be also used to measure the ion transport [163]. Planar bilayer had a size compatible to span lipid bilayer membranes. The
membranes (section 3.4.1) are ideal for the conductance study of ion standard base-pulse assay proved that this nanopore structure
channels using voltage clamp apparatus [164]. For water channels, had ionophoric activity. DNA origami has also been used to form
osmotic swelling and shrinking of vesicles, as completed in transport natural channel analogs (Fig. 16(e)) [179]. In the center of the DNA
studies of aquaporin, have been used to determine water perme- origami is a stem that consists of 6 double-helical DNA domains.
ability. None of these channels have been fabricated into planar This interior hollow tube inserts into bilayer membrane and serves
membranes yet and thus this area is still in its infancy. However, the as a transmembrane channel with a diameter of approximately
studies of articial channels not only contribute to a better under- 2 nm. The remaining 48 double-helical DNA domains are packed in
standing of the transport mechanism of membrane proteins, but honeycomb lattice and anchored to a lipid bilayer mediated by 26
could also generate powerful materials for future applications to drug cholesterol moieties that are attached to the cis-facing surface of the
delivery, catalysts, environmental sensors and membrane separa- barrel. The entire structure resembles the biological pore HL. This
tions. Articial channels can be classied into articial ion channels biomimetic channel was shown to have ion channels in single-
and articial water channels and they are discussed in detail in the channel electrophysiological measurements; and it was capable of
following subsections. discriminating single DNA molecules. This type of channel has been
incorporated into solid-state nanopore membranes as a novel bio-
3.4.3.1. Articial ion channels. Articial ion channels have been ltration/sensing device [160].
studied for approximately three decades [165]. Inspired by
biological ion channels, hundreds of different synthetic
structures have been synthesized so far. Current approaches are
based on chemical synthesis and supramolecular assembly 3.4.3.2. Articial water channels. Articial water channels that have
mimicking biological macromolecules such as polypeptide and nanotubular structures may be designed to selectively transport water.
DNA. Detailed description of the synthesis chemistry and analysis These channels are of particular importance since they might lead to
can be found in several excellent reviews [67,164,166]. Here we the new generation of water purication materials. However,
use a modied classication based on that provided by Matile in compared to the diverse structures of synthetic ion or solute
his latest review covering the breadth of this eld, which divides channels, articial water channel is still an emerging eld. This is
these channels into macrocycles, peptide-based, -stacks, metal because of the lack of the available architectures that can accurately
organic framework-based and DNA-origami-based channels [165]. mimic the structure and function of natural water channel proteins
We describe one representative channel of each category based on such as aquaporins [68,180]. The basic mechanisms responsible for
this classication. These channels have shown excellent lipid water transport in aquaporins have been well studied (see Fig. 9(a))
membrane spanning and ion conductance properties and have [64,65]. However, to design and build an articial analog of water
been incorporated into planar membranes [160]. channel proteins has proven to be a challenge. Current synthetic water
Crown ether macrocycles are widely used articial ion channels channels can be divided into two categories: (1) carbon nanotubes
because of their strong afnity for certain ions. However, single (CNTs) and (2) organic building block nanochannels (organic
crown ethers cannot span membrane bilayers. Amphiphilic chains nanochannels). CNTs have attracted much attention because they
are coupled with the crown ethers to provide membrane spanning show fast water transport, which is higher than conventional
domains (Fig. 16(a)) [167]. The resulting structure can be compatible HagenPoiseuille ow. The fast ow rate has been demonstrated
with the dimension of a bilayer. Other macrocycles include cyclo- using both experiments and molecular dynamic simulations [181,182].
dextrin [168], resorcinarenes [169], calixarenes [170], pyrogalloar- The reasons for high ow are related to atomic smoothness and single-
enes [171], cucurbiturils [172], and porphyrins [173]. Peptide-based le transport, which is similar to that observed in aquaporins. Organic
tubular structures are based on mimicking natural protein second- nanochannels are assembled from organic subunits via noncovalent
ary structures: -helical and -barrel. Matile and coworkers rolled forces such as hydrogen bonds, electrostatic, hydrophobic,  and
planar -sheets made of a sequence of amino acids with the same ion interactions. There are only ve structures that have been
372 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

Fig. 16. Articial ion channels: (a) A biomimetic ion channel consisting of a central crown coupled with three amphiphilic chains on each side to produce a bilayer-spanning
domain. Reproduced with permission from Ref. [167]. Copyright 1989 American Chemical Society; (b) peptide tubular ion channels formed via rolling planar -sheets made
of a sequence of amino acids for sugar sensing. Reproduced with permission from Ref. [174]. Copyright 2005 American Chemical Society; (c) G-quadruplex ion channel made
of guanosine derivatives. The tubular structure was due to the interaction between each cyclic tetramer with several other cyclic tetramers stacking on top of each other.
Reproduced with permission from Ref. [175]. Copyright 2005 American Chemical Society; (d) a synthetic ion channel made of a dimer of two Re (I)-porphyrin metal-organic
frameworks associated via hydrogen bonding. Reproduced with permission from Ref. [178]. Copyright 2012 American Chemical Society; (e) schematic illustration of the
channel formed by 54 double-helical DNA domains packed on a honeycomb lattice and the cross-sectional view through the channel when incorporated in a lipid bilayer.
Cylinders indicate double-helical DNA domains. Red denotes transmembrane stem; orange strands with orange ellipsoids indicate cholesterol-modied oligonucleotides that
hybridize to single-stranded DNA adaptor strands. Reproduced with permission from Ref. [179]. Copyright 2012 Science.

studied and published so far; they have pore sizes in the range 14.5 (Fig. 17(b)) [185]. The channel formed was reconstituted into
of 310 and thickness in 34 nm (Fig. 17). lipid giant unilamellar vesicles to prove that the channel was capable
Fei et al. synthesized a channel based on zwitterionic coordina- of selectively transporting water molecules against other solutes using
tion polymers using a reaction between N, N0 -diacetic acid imida- visual optical microscopy and osmotic shock experiments [184].
zolium bromide and zinc (Fig. 17(a)) [183]. The zinc polymer units Inspired by the (His37)4 selectivity lter in M2 proton channel
were linked by bridging dicarboxylate anions, which assembled into from inuenza A virus, Barboiu and coworkers synthesized imi-
helical channels and were supported by weak stacking interac- dazole compounds with urea ribbons that can self-assemble into
tions between the imidazolium moieties and by intrahelical hydro- tubular architectures by inner stacking and strong hydropho-
gen bonds. The two polymer molecules constitute a full cycle bic interactions. These channels are stabilized by strong hydrogen
within the helix with the distance between the layers of 6.2 . bonding with inner water in the solid state (Fig. 17(c)) [186]. Four
The structure determined by X-ray diffraction and solid-state NMR imidazole compounds in rhomboidal shape formed a gap in the
measurements show a single le water chain inside the channel and channel of 2.6 , which is very close to the narrowest constriction
constriction sites with dimensions approaching 2.6 in diameter. observed in some aquaporins. When these channels are reconsti-
The authors hypothesize that the transport rate of water should be tuted in lipid bilayers, they are able to transport water.
much lower than natural water channels because of the presence of In a recent contribution by Hou and coworkers, the hydrazide-
hydrogen bonds between the encapsulated water molecules and appended pillar[5]arenes and their derivatives were shown to form
the inner oxygen atoms of the channel. tubular structures as single-molecular water channels of  6.5 in
In 2007, Percec and coworkers [184] utilized self-assembled diameter (Fig. 17(d)) [187]. Water transport was demonstrated by
dendritic dipeptide to form stable cylindrical helical pores via inserting these channels into lipid vesicles and conducting time-
enhanced peripheral -stacking, with an inner pore diameter of resolved dynamic light scattering measurements. The alternative
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 373

Fig. 17. Articial water channels: (a) Helical tube formed by zwitterionic coordination polymers with the one-dimensional water chain in the center. Reproduced with
permission from Ref. [183]. Copyright 2005 Wiley-VCH; (b) cross-section of the helical pore assembled from dendritic dipeptides [184]. Reproduced with permission from
Ref. [185]. Copyright 2004 Nature Publishing Group; (c) cross-section views of imidazole I-quartets generating water channels, in which the water molecules present a
unique dipolar orientation. Reproduced with permission from Ref. [186]. Copyright 2011 Wiley-VCH; (d) tubular structures of pillar[5]arene derivatives used as water
channels. Reproduced with permission from Ref. [187]. Copyright 2012 American Chemical Society; (e) macrocycles for assembling into hydrogen-bonded nanotubes and a
snapshot of a helical stack of the macrocycles at the end of the 5 ps quantum molecular dynamics simulation. Reproduced with permission from Ref. [188]. Copyright 2012
Nature Publishing Group.

hydrophobic/hydrophilic domains along the cylindrical channel (PANCHEMA) asymmetric membrane surface via a reaction of hydro-
structure disrupted water wires, which may be responsible for xyl groups on the surface with 2-chloro-2-oxo-1,3,2-dioxaphospholane
blocking the proton ux in the channels. (COP) followed by a ring-opening reaction of COP with trimethylamine
Zhou et al. (Fig. 17(e)) [188] assembled macrocycles into (Fig. 18(a)) [206] This concept is inspired by the cell phospholipid
nanotubular building blocks based on the interplay of multiple membrane or specically zwitterionic phosphocholines on the cell
hydrogen bonding and stacking interaction (-conjugated hexa surface that show antifouling properties. The relative ux reduction
(m-phenylene ethynylene)). The resultant nanotubes had a uni- (fouling) was reduced by 15% after the membrane surface was
form diameter of 6.4 determined by the constituent macrocycles. anchored with phospholipid moieties. Glycosylation on the cell
The reconstituted nanotubes in lipid membranes not only facili- membrane surface has dual effects that it can recognize certain
tated highly selective ion transport, but also generated high water proteins while rejecting the others. Following this idea, a ring-
permeability. opening glycomonomer (D-gluconamidoethyl methacrylate, GAMA)
was grafted onto the surface of polyacrylonitrile membrane by
3.5. Bio-inspired antifouling separation membranes ultraviolet-initiated grafting polymerization (Fig. 18(b)) [207]. The
modied membranes, with improved hydrophilicity and biocompat-
For decades, enormous efforts have been made to enhance the ibility, were proved to have higher protein solution permeability and
fouling resistance via surface modication in medical [189191], better ux recovery after cleaning. However, most these studies are
marine [192194] and other industrial elds [82,83,195]. Particu- achieved for model protein solutions rather than highly complex
larly in membrane separation, there are many excellent articles plasma or serum containing hundreds of different proteins [191].
[196200] and books [201,202] introducing cutting-edge research Recent report by Gunkel and Huck demonstrated current excellent
and the related applications in this area. Most of these studies are antifouling surfaces (polyether-based brushes, side-chain zwitterionic
not commonly considered biomimetic in its narrow sense, so they polymers and hydroxylated polymers) suffered from the fouling from
are not included in this review. Here we only summarize the human blood plasma, regardless of the different polymer structures
antifouling membranes specically utilizing the two bioinspired [213]. There is still a need of deeper understanding of the interactions
approaches: (1) surface modication with bio-inspired molecules, between different proteins and modied antifouling surfaces in the
providing an energy barrier for foulants attachment to membrane areas of biomaterials research.
surfaces, (2) modifying the surface topography to achieve super- In membrane distillation, a hydrophobic membrane separates
hydrophobicity or superhydrophilicity: this approach changes water vapor from dissolved materials. In order to increase the water
surface morphology to control attachment between surface and productivity, a larger driving force (temperature gradient) and a
foulants. large pore size are preferred. However, this may result in the
Xu and coworkers modied a series of microporous membranes leakage of impure liquid phase entering the permeate side. It is
via chemically grafting bio-inspired brushes onto membrane surface thus vital to improve the hydrophobicity of the distillation mem-
[203207]. The brushes can be classied into three groups: polyethy- brane to prevent wetting. Shifting from conventional hydrophobi-
lene glycol related polymers [203,204,208,209], phospholipid city toward superhydrophobicity can introduce an air gap between
analogs [206,210] and sugar moieties [205,207,211,212]. Here we give liquid and the membrane surface, which prevents foulants from
two examples. Polymers derived from phospholipid analogs were getting in contact with the membrane [214]. This idea is designed
anchored onto the poly(acrylonitrile-co-2-hydroxyethyl methacrylate) by mimicking the surface morphology of superhydrophobic lotus
374 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

Fig. 18. Biomimetic antifouling membranes using surface modication: (a) poly(acrylonitrile-co-2-hydroxyethyl methacrylate) (PANCHEMA) ultraltration membrane
grafted with phospholipid analogs polymer chains. PANCHEMA06, PANCHEMA09 and PANCHEMA18 mean that 2-hydroxyethyl methacrylate contents in PANCHEMA are 6.4,
9.3 and 17.8 mol%, respectively. The relative ux reduction was measured at 1 MPa before and after the PANCHEMA membranes were anchored with phospholipid moieties.
Reproduced with permission from Huang et al., 2006 [206]. Copyright 2006 Elsevier Ltd.; (b) Polyacrylonitrile ultraltration membrane grafted with a ring-opening
glycomonomer D-gluconamidoethyl methacrylate (GAMA). With the grafting degree increased from 0 to 350.1 g/cm3, the relative ux reduction drop from 81.7% to around
24%. Reproduced with permission from Dai et al. [207]. Copyright 2008 Elsevier Ltd.

leaves, which relies on epicuticular wax microstructure to repel hydrophobic membrane [217]. Huang et al. [218] controlled the
water drops [215]. Ma et al. fabricated a superhydrophobic glass cooling rate during the formation of polytetrauoroethylene mem-
distillation membrane with highly ordered arrays of nanospiked brane, with specic micro-nano structures (Fig. 19(c)). The resulting
microchannels through a series of processes involving glass ber superhydrophobicity made the membrane very porous and
drawing, dissolving template material from microchannels and permeable.
differential chemical etching (Fig. 19(a)) [216]. The membrane also Surface modication to achieve superhydrophilicity is another
had a narrow pore size distribution. Both approaches allowed for antifouling strategy, which is suitable for aqueous separation mem-
reducing pore wetting by liquid while maximizing pore sizes to branes. Superhydrophilic surfaces attract water molecules and form a
increase the permeability. The modied membrane properties tightly bound hydration layer, thus protecting membrane from
reached water contact angle over 1601 with 90% of the pore foulants [82]. This approach has been achieved via immobilizing
diameters falling in the range of 34 m. The superhydrophobic superhydrophilic nanoparticles such as calcium carbonate or silica.
membrane showed higher ux than other polymeric membranes Chen et al. utilized poly (acrylic aid) brushes, which were negatively
under the same conditions. The superhydrophobic spiked nanos- charged, to induce the deposition of superhydrophilic CaCO3 nano-
tructures on the membrane surface also retarded fouling by redu- particles onto microporous polypropylene membrane. The modied
cing liquid-membrane contact areas. For conventional polymer membrane obtained excellent water permeability and ultralow
membranes, depositing nanoparticles or modication during mem- operational pressure [219]. Tiraferri at el. incorporated superhydro-
brane fabrication can be also used to achieve superhydrophobic philic  N(CH3)3 functionalized silica nanoparticles onto thin-lm
surface. Razmjou et al. deposited TiO2 nanoparticles onto polyviny- composite polyamide membranes via chemical crosslink [220]. The
lidene uoride membranes and obtained superhydrophobic mem- relative ux decline of the modied membranes was approximately
branes with contact angle around 1601 (Fig. 19(b)) [214], which 1015% less in both forward osmosis and reverse osmosis modes,
signicantly improved the antifouling properties. It also increased compared to the averaged relative ux decline of the control
the liquid entry pressure, which is dened as the pressure differ- membranes. The superhydrophilic membranes also showed 95
ence from which the liquid penetrates into the pores of the 100% ux recovery after cleaning.
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 375

Fig. 19. Biomimetic antifouling strategies based on surface topography design: (a) Scanning electron microscopy (SEM) image of nanospiked microchannels made by etching
a polished glass plate in a 1% hydrouoric acid solution for 30 min. Reproduced with permission from Ref. [216]. Copyright 2009 American Chemical Society; (b) SEM image
of TiO2 nanoparticle deposited polyvinylidene uoride membranes. Reproduced with permission from Ref. [214]. Copyright 2012 Elsevier Ltd.; (c) micronano structures of
polytetrauoroethylene membranes produced at different cooling rates. Reproduced with permission from Ref. [218]. Copyright 2013 The Royal Society of Chemistry.

Table 3
Challenges to development and scale-up of various biomimetic membranes.

Practical challenges Fundamental challenges Current status

Biomimetic nanopores (solid state) Scale-up at reasonable cost Selection of functionalization Commercialization attempts
ligands to provide selectivity for DNA sequencing [223];
no separations applications yet

Carrier mediated Liquid membranes Stability; process conguration Low transport rates Not commercialized
biomimetic membranes Ionophore based Low transport rates ;would Overcome, but transport rates low Electrodes for sensing
membranes require large membrane areas for separations applications commercialized;
no separations applications

Membrane protein mediated Membrane protein production Limited range of proteins Commercialization
biomimetic membranes scale-up; large area membrane and polymers attempts ongoing
scale-up; leakage prevention

Articial channel membranes Scale-up Designing specicity into channels, New research area for
packing channels in membranes, water channels, ion channels
increasing permeability studied but not commercialized

Antifouling strategies Cost and efcacy Not substantial for most Various stages of research and
applications commercialization

4. Challenges and opportunities for biomimetic membranes 4.2. Carrier mediated biomimetic membranes

The following section presents a brief overview of the chal- Carrier mediated biomimetic membranes include LMs and
lengesboth fundamental and practical, as well as the current ionophore based membranes. LMs have interested researchers in
status of biomimetic membrane technologies. This is also sum- the last few decades as described earlier and an excellent under-
marized in Table 3. A specic focus of this section is aquaporin standing of the transport process has developed. However, com-
based membranes that has seen substantial research activity mercialization efforts in separations have been hindered by the
recently including a few ongoing commercialization attempts poor stability and other practical difculties in implementation
[221,222]. process. These practical difculties include unstable immobiliza-
tion of LMs in SLMs and process inefciencies in separation of the
recovered materials from the emulsion phase in ELMs. Never-
theless, some applications have been scaled up to the pilot scale
4.1. Biomimetic nanopores and larger in recent years. ELMs have been used for zinc, phenol
and cyanide removal from industrial waste streams [51].
Biomimetic nanopores including those created with solid-state Ionophore based membranes are widely used in ion selective
materials such as silicon is a new research area. Scale-up to practical electrodes. Ion selective membranes are the gold standard for this
dimensions for separation applications could face several challenges. application. However, their application in separation membranes has
Making nanoscale pores using current methods such as i-beam and not yet progressed due to the low transport rates of ions in practical
e-beam lithography is currently a lab scale process and requires polymeric matrices [224]. In order to provide uidity to the polymer
expensive infrastructure. Furthermore, a fundamental challenge still matrix, plasticizers are used but these still do not improve the
being explored is that the functionalization of these pores using transport to reasonable levels for separation applications.
specialized biological molecules and chemistry, which may be
difcult to implement on larger scales. Questions regarding the 4.3. Membrane protein mediated biomimetic membranes
ligands that can be used to functionalize pores are also challenging
to address particularly if ion discrimination, such as those seen in Membrane protein-based biomimetic membranes, in particular
potassium channels, is desired. However, their application to DNA aquaporin based membranes, have seen a large increase in interest
sequencing has reached commercialization levels with several tech- in recent years and there are a few attempts at commercialization.
nologies licensed to start-up organizations [223]. This is also the subject of a recent review [25]. However, there are
376 Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381

several fundamental and practical challenges that still need to be and used widely primarily for laboratory research are: E. coli, yeast
addressed before large-scale membranes suitable for applications (Pichia pastoris and Saccharomyces crevisiae), baculovirus infected
can be developed. These are discussed in the paragraphs below. insect cells (e.g., Sf9 cells from Spodoptera frugiperda) and mam-
Application of aquaporin biomimetic membranes face many malian cells (Chinese hamster ovary cells in particular). However,
fundamental challenges, primarily because of the limited scope of membrane protein production is limited both by the ability of the
fundamental studies conducted in this area so far. In particular, cells to survive membrane protein overproduction and due to the
BCPs that have been used for inserting membrane proteins have lack of coordination between membrane protein production and
been primarily limited to a single polymer type with polydi- cell membrane production to accommodate membrane proteins.
methylsiloxane (PDMS) hydrophobic block [65]. Recent reports Alternative approaches to producing membrane proteins in gen-
have shown that the mammalian eye lens aquaporin (AQP0) was eral and aquaporins in particular should be further explored.
incorporated into PB-PEO BCP membranes with success [69]. The primary practical challenge is in the scale-up of defect free
While these polymers have been shown to insert membrane membranes. So far the sizes that are being realized are in the scale of
proteins, it is not well understood what dictates membrane mm2 even though rapid strides are being made in this direction
protein polymer interactions and compatibility. Perhaps other [25,142,143,145154]. The methods used for membrane fabrication-
polymers with superior characteristics have not been explored vesicle deposition, monolayer formation, and pore suspended bilayers
because a rational basis for polymer selection does not exist. More are all challenging to replicate at higher scales. Also most substrates
experimental and theoretical explorations are required to inform used for supporting or immobilizing active AqpZ containing mem-
this rapidly growing eld. branes are specialized ranging from gold coated track-etched mem-
A related question to this is that how to quantify insertion branes [147,153] to polymer based membranes [146,148152,154].
efciency of membrane proteins in BCPs in order to determine the The more scalable approach is the use of polymer membranes if
best polymer (most compatible) for a particular membrane pro- technical hurdles to sealing around deposited vesicles and bilayers are
tein. No assay currently exists for quantifying the amount of solved.
protein inserted per unit membrane area with sufcient accuracy. The economics of making such membranes is challenging.
Biochemistry based methods such as western blotting [225,226], Membrane protein purication is expensive primarily due to the
antibody-gold labeling [227], and freeze fracture [228] are challen- need to disrupt cell membranes, use of specialty nonionic deter-
ging to implement and do not provide quantitative information. A gents, ultracentrifugation, and chromatography. A thorough ana-
new method is needed to accurately determine insertion efciency lysis of membrane protein scale-up has not been conducted before
and thus compatibility of membrane proteins in various polymers and should be a thrust if this class of membranes progresses to
to provide a rational basis for BCP selection. larger scales of production and commercialization. Another chal-
A successful biomimetic membrane would require high levels lenge may be the unknown landscape of regulation regarding the
of protein packing in membranes. In most studies, full function of use of membrane proteins, particularly in water treatment appli-
aquaporins in BCP membranes has only been demonstrated at cations. The possibility of release of these materials is real and may
packing densities that are relatively low, when the concentration be regulated. This challenge is similar to that faced by membranes
of membrane proteins in native membrane systems such as eye that incorporate nanomaterials.
lenses, the retina, and bacterial photosynthetic membranes is
considered. A typical packing density showing the expected 4.4. Articial channel based membranes
function was demonstrated for AqpZ reconstituted into poly-
(2-methyloxazoline)-block-poly-(dimethylsiloxane)-block-poly- Articial channel based biomimetic membranes are a relatively
(2-methyloxazoline) (PMOXA-PDMS-PMOXA) triblock copoly- new research area and most work has been focused on their
mer membranes at a molar polymer to protein ratio (mPoPR) synthesis and characterization. Transport measurements are still
adjusted for triblock architecture of 50100, beyond which rudimentary in this eld [165] and more studies are needed to be
permeability has been shown to decrease [133]. In a recent able to compare their efciency to membrane protein channels.
study, AQP0 function was shown to persist at a mPoPR of 15 in a Articial water channels attract interest since they might be the
PB-PEO polymer [69]. This study also show that the reconstitu- novel materials for water purication. The challenges of CNTs for
tion method is critical, but polymer block lengths and chemis- desalination applications, where it could have the most impact,
tries may also be important factors that determine how much include non-sufcient salt rejection and the challenge to inherent
protein can be functionally reconstituted into BCP membranes. in manufacturing large-sale aligned CNT membranes [235].
The possibility to obtain a high density of functional membrane Organic nanochannels based water channels, in particular, are just
proteins in BCP membranes has signicant implications for applica- beginning to be explored. To date, there are no specic guiding
tions of such systems. High protein packing has been shown in lipid principles for the design, as can been seen from the ve channels
bilayers by studies that investigate membrane protein structure discussed above [183,184,186188]. The only semi-empirical prin-
using 2D crystallization [229231] and several native membranes ciple is mimicking natural selective lters. However, the current
described earlier [229,232,233]. A better understanding and char- structures are still far from perfect. Current data indicates that
acterization of membrane protein-BCP compatibility will also assist they suffer from low permeability (4 3 orders of magnitude lower
in making highly packed aquaporin based membranes similar to than aquaporins) and possibly imperfect rejection of solutes in
lipid-based membrane protein 2D crystals. There is also a need to some cases where channel diameters are large [187]. As men-
explore aquaporins beyond the traditionally used Escherichia coli tioned by Fei et al., extensive hydrogen bonding helps encapsulate
AqpZ, which may have perhaps higher permeability and or better water wires within the channel, but also reduces the mobility of
insertion efciency in BCPs. water molecules. This is probably the reason why the channels
Another fundamental challenge is the use of systems for showed very low water permeability ( 44 orders of magnitude
expressing large amounts of membrane proteins. AqpZ is well lower than lipid background permeability). This also leads to
expressed in E. coli and yields of up to 200 mg L  1 of culture in a another challengeHow to measure the permeability of low
fusion form have been reported [234]. This is promising for scale- permeable channels? A systematic platform for water permeabil-
up of this particular aquaporin. In general for membrane proteins, ity measurement should be established [165]. The next generation
yields are much lower (typically 1 mg L  1 of culture). The major of water channels is expected to improve the design of the pore
membrane protein expression systems that have been developed structure in order to increase the water permeability while
Y.-x. Shen et al. / Journal of Membrane Science 454 (2014) 359381 377

maintaining or improving solute rejection. The geometry of the major opportunities that we think provide an impetus for accelerated
channels is also one possible area of improvement, which will research and development in the area of biomimetic membranes
assist in packing these channels with very high density in lipid or include: (1) use of synthetic biomimetic channels in membrane
polymer matrix for membrane fabrication. matrices, (2) bioinspired approaches for membrane fouling preven-
None of these ion or water channels have been tested in a tion, and (3) utilization of novel biological materials interfaced with
practical membrane like form as they are currently being studied stable synthetic materials.
in lipid vesicles. However, they hold great promise for separation While membrane protein-based membranes have captured the
applications due to their higher stability, properties potentially imagination of many researchers in this eld and there is sub-
matching natural channels, scalability of their production and stantial progress towards scale-up, performance enhancement and
ability of immobilization in membrane-like supports in a scalable commercialization of this technology, an exciting alternative could
manner. be organic building block based articial channels. We are rapidly
gaining a better understanding of the structure and function of
4.5. Biomimetic antifouling strategies membrane proteins. At the same time, our ability to design
supramolecular and self-assembled structures is increasing. We
Bioinspired antifouling strategies proposed for existing mem- are approaching a stage in channel research where some of the
branes are also generating interest in this eld. Many of the intricate functions provided by membrane proteins can be recapi-
approaches proposed, specically surface modication, seem to tulated by articial structures. These could be better engineering
be technically feasible. A cost benet analysis and their practical materials for membranes from the perspective of mechanical,
implementability may be important to consider advancing them chemical and biological stability while providing many routes for
to the application level, particularly because some of these functionalization and incorporation in to membranes through
approaches decrease the initial permeability of membranes. synthetic chemistry.
Bioinspired approach to membrane fouling mitigation is
another promising area of research. Fouling, especially biofouling,
5. Outlook for biomimetic membranes is a challenging problem that persists despite the application of
chemicals and use of novel materials and operational strategies.
Research and development in biomimetic membranes has Biological molecules evolve to colonize the most challenging man-
reached a promising stage. Several technologies are being devel- made surfaces, while many biological systems seem resistant to
oped that could advance the state of the art in membrane separa- severe fouling. Thus, lessons learnt from biolm control, preven-
tions. However there are many challenges to overcome before this tion and dispersal in biological systems may be valuable for
technology can be considered mainstream. In our opinion, three preventing fouling. This could be a sustainable and powerful
major challenges for biomimetic membranes include the following: alternative to current approaches. In particular, the use of quorum
(1) a lack of fundamental understanding (for many of the technol- sensing for biolm dispersal seems promising and the use of
ogies discussed) of the interaction between functional molecules zwitterionic biofouling surfaces already seems to be approach
used and matrix materials, (2) scalability of current approaches to growing in popularity.
synthesis of biomimetic membranes, and (3) the cost for making We believe that the integration of biological materials with
large quantities of biomimetic materials. synthetic materials is still in its infancy with only simple biological
Fundamental understanding of materials' interactions such as molecules and proteins being incorporated into relatively simple
membrane proteins, articial channels, bio-based coating materi- polymers and solid state constructs. There are new proteins with
als and biomimetic polymer brushes with commonly used and novel functions being discovered almost on a daily basis and their
proposed membrane matrix materials such as polymers and atomic structures determined. Their integration within usable
silicon substrates is still largely unexplored. There is need for stable matrices and hierarchical systems with many layers of
further systematic research into the interactions, compatibility and control could still be the most straight forward way to construct
long-term stability of biomimetic hybrid assemblies such as membrane systems, which may one day reach the complexity,
membrane proteinBCP membranes and composites such as efciency and responsiveness of model organ systems such as the
functionalized solid-state nanopores. This information is critical kidney.
to the two other challenges identiedscalability and costs.
Many biomimetic membrane synthesis approaches are bottom-
up type processes that rely on self-assembly which are challenging Acknowledgments
to scale up. Because of this approach, the current dimensions of
many biomimetic membranes (not including antifouling functio- We thank Dr. Andrew Zydney for his critical reading of the
nalized membranes) are quite small from the nm2 to mm2 scale. manuscript and valuable suggestions.
Innovations are required to develop techniques for organizing
these self-assembled aggregates into functional membrane forms. References
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