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Review on biomedical and bioengineering applications of cellulose sulfate
Accepted Manuscript Title: Review on biomedical and bioengineering applications of cellulose sulfate Author: Qilei Zhang Dongqiang Lin Shanjing Yao PII: DOI: Reference:
S0144-8617(15)00548-2 http://dx.doi.org/doi:10.1016/j.carbpol.2015.06.041 CARP 10030
To appear in: Received date: Revised date: Accepted date:
30-4-2015 11-6-2015 12-6-2015
Please cite this article as: Zhang, Q., Lin, D., and Yao, S.,Review on biomedical and bioengineering applications of cellulose sulfate, Carbohydrate Polymers (2015), http://dx.doi.org/10.1016/j.carbpol.2015.06.041 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Highlights
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The preparation and application of cellulose sulfate was reviewed.
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Biomedical potentials of cellulose sulfate were emphasized.
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Future perspectives on cellulose sulfate development were summarized.
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Review on biomedical and bioengineering applications of cellulose sulfate
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Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College
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of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027,
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China
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Qilei Zhang, Dongqiang Lin, Shanjing Yao*
* Address for Correspondence:
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Prof. Shan-Jing Yao
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College of Chemical and Biological Engineering
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Zhejiang University
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Hangzhou, 310027
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China
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Tel: +86-571-87951982
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Fax: +86-571-87951982
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E-mail: [email protected]
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Abstract
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Polysaccharide sulfates are naturally existing chemicals that show important
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biological activities in living organisms. Cellulose sulfate is a semi-synthesized
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polysaccharide sulfate with relatively simple chain structure and unique biological
38
properties, and its biological applications have been explored in research and clinical
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trials. With the advance of cellulose derivatization and characterization, cellulose
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sulfate molecules with tailored structures have been developed to fulfill individual
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requirements. This review aims to provide a summary of recent development of
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cellulose sulfate in biomedical applications. Its synthesis pathways were discussed
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with structure-property relationship elucidated. The application of cellulose sulfate in
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drug delivery and microbe/cell immobilization were summarized with emphasis given
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on its polyelectrolyte complex formation processes.
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Keywords: cellulose sulfate; cellulose sulfation; antiviral; polyelectrolyte complexes;
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cell immobilization;
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1. Introduction
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Polysaccharides are widely available biological polymers with remarkable structural
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diversity. The unique backbone structure combined with good chemical amenability
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further makes polysaccharides valuable resources. Currently, polysaccharides find
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applications in almost every aspect of human life and with the functionality of
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polysaccharide structures, it has become an important material in textile, medicine,
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environmental protection, food and pharmaceutical industry (Lucia et al., 2012).
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Cellulose is a simple polysaccharide with no branching or substituents, which is often
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considered as the most abundant polymer in nature (Fox et al., 2011). It is massively
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produced with relative low cost and shows wide applications in both industry and
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academy (Glasser, 2004).
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The hydroxyl groups of cellulose can fully or partially react with chemical agents to
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obtain various derivatives with different degree of substitution (Habibi, 2014; Heinze
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et al., 2012b), and a series of cellulose derivatives like esters (El Seoud et al., 2005)
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and ethers (Nguyen et al., 2014) have been synthesized to meet specific requirements
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from industry. Table 1 listed some typical cellulose derivatives currently available.
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Due to structure similarity and biological origin, these esters and ethers have similar
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applications in food and pharmaceutical industry. Most of these derivatives are also
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mass produced.
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Cellulose sulfate is a semi-synthesized cellulose derivative with relatively simple
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chain structure and unique biological properties. Currently, it is still mainly produced
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in lab-scale with limited commercial applications. Nevertheless, research has shown
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that it can be applied as anticoagulant (Groth et al., 2001), antiviral (McCarthy, 2007),
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contraceptive (Anderson et al., 2004), Human Immunodeficiency Virus (HIV)
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microbicide (Stone, 2002), etc. These areas are hot spots for both academy and
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industry, and the potential markets make cellulose sulfate unique among cellulose
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derivatives. Similar biological activities of cellulose sulfate were originally found on
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some naturally occurring polysaccharide sulfates (Heinze et al., 2010). For example,
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Figure 1 shows the repeating units of heparan sulfate, chondroitin-6-sulfate and
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dermatan sulfate which are three important polysaccharide sulfates found in living
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organisms. Meanwhile, cellulose sulfate has certain advantages over natural
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counterparts, such as defined chemical structure and easy separation/purification,
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which make it suitable for industry scale production and application.
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This review would like to provide a summary of research on cellulose sulfate, and
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emphasis is given to its application in biotechnological and medical areas, especially
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the application of cellulose sulfate as a polyanionic polymer to form polyelectrolyte
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complex films or capsules with polycations. Material synthesis pathways are briefly
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reviewed and a future perspective is included to discuss challenges and prospects of
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cellulose sulfate.
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Application
Hydroxyethyl cellulose
-CH2CH2OH
Thickener；
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an
Cellulose derivatives
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Table 1. Examples of typical cellulose derivatives and their applications
pharmaceutical excipient -CH2CH(OH)CH3
Pharmaceutical
References
(Chronakis et al., 2002; Singh et al., 2003; Zulkifli et al., 2014) (Nguyen et al., 2011; Ogawa et al., 2014)
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Hydroxypropyl cellulose
excipient；lubricant； thickener
Thickener
d
cellulose
-CH2CH2OH, -CH3
ep te
Hydroxyethyl methyl Hydroxypropyl methyl
-CH2CH(OH)CH3,
Pharmaceutical
cellulose
-CH3
excipient； emulsifier；
(Mischnick et al., 2013) (Jain et al., 2014; Khan et al., 2013; Lamberti et al., 2013; Siepmann et al., 2012)
thickener
Ethyl hydroxyethyl cellulose
-CH2CH2OH,
Ac c
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Carboxymethyl cellulose
Methylcellulose
Emulsifier；
-CH2CH3
pharmaceutical excipient
-CH2COOH
Thickener； food
-CH3
(Calejo et al., 2013; Karlberg et al., 2005)
(Shlyapnikov et al., 2014; Tang et al., 2014)
additive； pharmaceutical excipient Thickener； emulsifier
(Lott et al., 2013; Noronha et al., 2014)
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-CH2CH3
(Cheu et al., 2001; Davidovich-Pinhas et al., 2015)
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Ethylcellulose
-COCH3
Coating；fiber
Cellulose propionate
-COCH2CH3
Coating；film
(Bianchi et al., 1997)
Cellulose acetate propionate
-COCH2CH3,
Fiber； paint
(Huang et al., 2011) (Huang et al., 2011)
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Cellulose acetate
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pharmaceutical excipient
-COCH3 -COCH2CH2CH3, -COCH3 -NO2
Cellulose sulfate
-SO3H
Fiber；film；explosive
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Cellulose nitrate
Fiber； paint
d
Cellulose acetate butyrate
(Caruso et al., 2000; Liu et al., 2002)
(Nartker et al., 2010)
Microbicide；
(Aggarwal et al., 2013; Neurath, 2008; Wang et al.,
anticoagulant；
1997)
pharmaceutical
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excipient； film
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ip t Figure 1. Repeating units of some naturally occurring polysaccharide sulfates and
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cellulose sulfate.
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2. Cellulose sulfation: processing strategies
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A series of synthetic procedures for the preparation of cellulose sulfate have been
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investigated and methods for cellulose sulfation were recently reviewed by Heinze et
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al. (Heinze et al., 2010; Heinze et al., 2012b). Therefore, detailed synthetic methods
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and procedures will not be discussed here. Generally, three synthetic strategies have
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been applied based on the solubility of substrates in reaction media. Table 2
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summarized some typical synthetic methods reported in the literature.
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2.1 Heterogeneous sulfation
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Cellulose is difficult to be dissolved in most solvents (Pinkert et al., 2009). Therefore,
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if cellulose is used as a raw material, sulfation process unfolds usually as a
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heterogeneous reaction. H2SO4 and propanol are the most used reactants for
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heterogeneous sulfation of cellulose (Yao, 2000), and recently Chen et al. (Chen et al.,
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2013) proposed a modified process that used ethanol to replace propanol to simplify
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the synthetic procedure and reduce cost. In order to restrain chain cleavage catalyzed
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by H2SO4, the reaction is usually performed below 0 oC. This restriction can be 8
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overcome by using SO3-complexes such as SO3-pyridine and SO3-DMF as the
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sufation agents, and dimethylformamide (DMF) is usually used as the solvent to
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suspend cellulose during reaction (Zhu et al., 2014). Since cellulose sulfate has to
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reach certain substitution degree to be dissolved in DMF, this method often results in
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products with high degree of substitution. The heterogeneous strategy uses simple raw
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materials with flexible preparation procedures. However, one problem for
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heterogeneous synthesis is non-uniform substitution. As cellulose is not fully
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dissolved, substitution mainly happens at the amorphous parts of cellulose with the
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crystalline part remain unreacted.
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2.2 Homogeneous sulfation
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Homogeneous strategy can overcome this non-uniform substitution problem after
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dissolving cellulose in certain solvents. Products from homogeneous synthesis usually
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have even distribution, good solubility, and low chain degradation (Qin et al., 2014).
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For example, N2O4/DMF was used for the synthesis of cellulose sulfate with
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SO3-complexes as reactants (Wagenknecht et al., 1993). Cellulose nitrite is first
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formed as an intermediate. It then reacted with SO3-complexes to obtain final
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products with different degree of substitution. Moreover, cellulose sulfate synthesized
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can be dissolved in water at very low degree of substitution (~0.3). However, N2O4 is
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toxic which limits large scale production and also the application of the product in
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biomedical areas (Gericke et al., 2009a). Meanwhile, ionic liquids have become
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extremely popular in research (Rogers et al., 2003) and some are good dissolution
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media for cellulose (Gericke et al., 2009b; Pinkert et al., 2009). Gericke et al.
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(Gericke et al., 2009a) used 1-butyl-3-methylimidazolium chloride (BMIMCl),
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1-ethyl-3-methylimidazolium acetate (EMIMAc) and 1-allyl-3methylimidazolium
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chloride (AMIMCl) in homogeneous synthesis of cellulose sulfate. The results
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showed that direct sulfation under completely homogeneous conditions was
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applicable. The minimum degree of substitution required for water solubility of the
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product was 0.25. It is worth to note that the cellulose-ionic liquid system usually has
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high viscosity which sometimes makes mixing problematic. Therefore, cosolvents are
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usually needed to reduce the system viscosity. Synthesis in ionic liquids seems a good
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pathway to prepare cellulose sulfate, but the high cost of ionic liquids needs to be
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aware when considering mass production.
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2.3 Quasi-homogeneous sulfation
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In addition to homogeneous synthesis, cellulose derivatives with better solubility than
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cellulose were used as reactants. Such strategies are referred as quasi-homogeneous
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synthesis and the properties of cellulose sulfate prepared are usually dependent on
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sulfation processes. Cellulose acetate, cellulose nitrite and trimethylsilyl cellulose
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(TMS) are three typical derivatives used and the main problem of this strategy is the
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complexity of reaction systems which need further effort for purification (Richter et
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al., 2003).
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The above discussed methods for cellulose sulfate synthesis are mainly for the
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preparation of sodium salts. The development of sulfated cellulose has been further
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explored in studying derivatives of cellulose sulfate (Heinze et al., 1999). For
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example, methylated cellulose sulfate (Gohdes et al., 1997), carboxyl cellulose sulfate
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(Zhang et al., 2010b), amino cellulose sulfate (Heinze et al., 2012a) and oxyethylated
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cellulose sulfate (Udoratina et al., 2012) were synthesized with their biological
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properties compared.
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Table 2. Typical pathways for cellulose sulfate synthesis. Typical chemical
Characteristics
Heterogeneous
H2SO4/propanol or
Low temperature is necessary; Non-uniformly
ethanol
substituted; Cheap raw material and good adjustability.
SO3-complex*/DMF
High degree of substitution; Non-uniformly
Cellulose acetate
Good
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substituted. Quasi-homogeneous
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Synthesis
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reactant
solubility;
Need
further
Trimethylsilyl (TMS)
Regioselective
anhydride
solubility; Need large amount of chemicals.
N2O4/DMF
Ionic liquid
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Negligible depolymerization.
SO3-complex/acetic
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Homogeneous
Degree of substitution is limited by TMS;
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cellulose
d
purification.
synthesis;
Good
water
Good reactant and product solubility; High solvent toxicity. Good
reactant
and
product
solubility;
Uniform substitution; High viscosity.
Reference (Bhatt et al., 2008; Chen et al., 2013; Yao, 2000) (Zhu et al., 2014) (Zhang et al., 2009) (Richter et al., 2003) (Zhang et al., 2011a; Zhang et al., 2011b) (Wagenknecht et al., 1993) (Gericke et al., 2009a; Liebert et al., 2009; Tao et al., 2011)
*: SO3-complex can be SO3-DMF, SO3-pyridine, ClSO3H, etc.
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With the development of modern chemistry, fine manipulation of molecule becomes
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possible and sometimes needed to obtained chemicals with specific properties.
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Reaction conditions are milder when cellulose is fully dissolved that breaks extensive
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H-bonds, which make it possible for regioselective and regiospecific synthesis of
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cellulose derivatives (Fox et al., 2011). The regioselective synthesis of cellulose
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sulfate has been reviewed (Baumann et al., 2003; Fox et al., 2011; Klemm et al.,
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1997), and heterogeneous, quasi-homogeneous and homogeneous strategies have all
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been applied with various reactants and solvent systems. However, many researchers
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only use 1H and 13C NMR spectra data to support the regioselective synthesis, which
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are not always convincing. Therefore, it is also important to develop a comprehensive
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characterizing package for such research (Gohdes et al., 1998).
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3. Structure-property relationship
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Like many other polymers, the physical, chemical and biological properties of
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cellulose sulfate, such as water solubility, chemical reaction and biological activity are
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largely dependent on the molecular weight, the degree and distribution of substitution
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along polymer chains (Heinze et al., 2010). It has been noted that the quantification of
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cellulose sulfation remains challenging(Gu et al., 2013). Several characterizing
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techniques have been applied in structure study. For example, Raman and infrared
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spectroscopy were used to measure substitution degree (Petropavlovskii et al., 1971;
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Zhang et al., 2010a). The correlation between certain Raman vibration signals with
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total degree of substitution was built and the correlation results were compared with
194
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which indicated that Raman spectroscopy can be a potential rapid method for
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quantifying degree of substitution (Zhang et al., 2011a). Zhu and Yao (Zhu et al.,
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C nuclear magnetic resonance (NMR) spectroscopy and elemental analysis results,
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2012) compared polyelectrolyte titration, BaSO4 turbidimetry and elemental analysis
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methods in the measurement of substitution degree. They found that BaSO4
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turbidimetry and elemental analysis can provide similar results, but the polyelectrolyte
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titration lacked consistency. Moreover, the distribution of sulfate group is an
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important physical factor that can affect water solubility of cellulose sulfate. Gohdes
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and Mischnick (Gohdes et al., 1998) used a series of methods including
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permethylation, desulfation, deuteromethylation, random cleavage, remethylation, and
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fast-atom bombardment mass spectrum to determine the substitution pattern of
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cellulose sulfate by analysis of degraded samples. Cellulose sulfate prepared from
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seven different sulfation processes were compared. Their work provided detailed
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results about positions of sulfated groups on cellulose chains. Two-dimensional 1H
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and 13C NMR spectroscopy (Kowsaka et al., 1991) and mass spectrometry (Mischnick
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et al., 1999) were also applied in the determination of substitution distribution.
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Moreover, the molecular weight of cellulose sulfate can be measured by low angle
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laser light scattering (LALLS) and gel permeation chromatography (GPC) (Wang et
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al., 2009b; Zhu et al., 2012), while LALLS has advantages of measurement without
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standard polymer samples. Other properties of cellulose sulfate such as liquid crystal
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formation were also discussed in literature studied by differential scanning
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calorimetry (DSC) and X-ray diffractometry (Hatakeyama et al., 1995; Onishi et al.,
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2009).
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The performance of polymer materials in various applications is usually closely
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related to their structures. Table 2 shows that the structure properties are most likely
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determined by the reaction pathways. Heterogeneous synthesis usually results in the
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formation of non-uniform substitution distribution, which is due to the solubility
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difference of amorphous and crystalline parts of cellulose in solvents. Meanwhile, the
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degree of substitution is affected by reaction type and time. For examples, the
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relationship between degree of substitution, percentage of water soluble parts and
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viscosity was studied under heterogeneous synthesis with H2SO4/propanol mixtures
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and the results can be schematically depicted (see Figure 2) (Heinze et al., 2012b). It
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seems reasonable that with the increase of soluble part percentage and degree of
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substitution, the viscosity of cellulose sulfate decreases.
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Figure 2. Relationship of viscosity, degree of substitution and soluble part percentage
230
of cellulose sulfate synthesis by heterogeneous pathways.
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The effect of sulfate groups on the properties of cellulose sulfate has been widely
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studied, especially on sulfated nanocrystalline cellulose. For example, Voronova et al.
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(Voronova et al., 2013) prepared films composed of nanocrystalline cellulose sulfate
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and the relationship between film property and sulfate group contents was studied.
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The results showed that both surface roughness and water adsorption ability enhanced
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with the increase of sulfate group. Jiang et al. (Jiang et al., 2013) used sulfated
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cellulose as substrates for cellulase to study the effects of sulfate group on cellulase 15
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adsorption and enzymatic hydrolysis. They found that the surface accessibility was
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similar with different sulfate group density, but the binding domain decreased. An
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inhibitory effect of sulfate group in enzymatic hydrolysis was discussed. Moreover,
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the effects of sulfate groups on the thermal degradation of cellulose was studied (Lin
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et al., 2014; Roman et al., 2004). The results showed that the degradation temperature
244
was significantly decreased with the sulfation of cellulose, and the sulfate group
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showed a catalytic effect on cellulose thermal degradation. Lokanathan et al.
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(Lokanathan et al., 2013) used cellulose nanocrystals to assist the synthesis of silver
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nanoparticles. The results showed that cellulose after sulfation can stabilize silver
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nanoparticles formation and the decrease of substitution resulted in narrower
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nanoparticle size distribution. Moreover, Cellulose sulfate with high degree of
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substitution has shown potential application as Microbicides (Anderson et al., 2002;
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Yoshida, 2001; Yoshida et al., 2001).
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4. Biomedical applications of cellulose sulfate
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4.1 Biological activity
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Polysaccharide sulfates in living organisms were early found playing certain roles in
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their biological activities, such as antiviral and blood coagulation(Ghosh et al., 2009;
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Kindness et al., 1980). Currently, various semi-synthesized polysaccharide sulfates
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have been developed and similar biological behaviors are also found from these
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materials, such as chitosan sulfate, dextran sulfate and cellulose sulfate (Groth et al.,
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2001). This review is focused on the application of cellulose sulfate with some typical
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biological activities and related applications summarized in Table 3.
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4.1.1 Anticoagulation 16
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Natural heparin is a widely used anticoagulant in clinical application but shows
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certain side effects (Han et al., 2005). Therefore, development of alternatives like
266
cellulose sulfate is important. Moreover, cellulose sulfate has well defined structure
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and lack of branches on polymer chains, which is good for quality control and
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structure-activity research. Wang et al. (Wang et al., 2007) found that cellulose sulfate
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showed higher anticoagulation activity than heparin under their experimental
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conditions, and in vivo studies revealed that the anticoagulation activity of cellulose
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sulfate was achieved by accelerating the inhabitation of antithrombin III on
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coagulation factors in plasma. Similar anticoagulation mechanism was discussed by
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Grombe et al. (Grombe et al., 2007). The effects of molecular weight and sulfate
274
group distribution on anticoagulation were also investigated (Wang et al., 2005; Wang
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et al., 2010c). Although it was revealed that molecular weight was important in the
276
anticoagulation application, their in vitro and in vivo results seem controversial and
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further research may be necessary in studying the structure-activity relationship.
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4.1.2 Antiviral: HIV treatments
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Antiviral has a large market in pharmaceutical industry and is a major focus for
281
biotech companies (McCarthy, 2007). Among newly developed antiviral substances in
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recent years, sulfated polysaccharides are often highlighted. Some aspects of their
283
antiviral activity have also been elucidated, which becomes clear that the charge
284
density and chain length are not the only contributors in their antiviral performance
285
(Ghosh et al., 2009). Cellulose sulfate is one of the most reported sulfated
286
polysaccharides in antiviral investigation, which may mainly be attributed to a
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commercial drug candidate named UshercellTM. It is a high molecular weight form of
288
cellulose sulfate developed by Polydex (Canda) and was found active against human
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immunodeficiency virus (HIV), herpes simplex virus (HSV), Neisseria gonorrhoeae,
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Chlamydia trachomatis, papillomaviruses and gardnerella vaginalis (Anderson et al.,
291
2004). UshercellTM also shows contraceptive in preclinical evaluations (Anderson et
292
al., 2002) and it has excellent safety performance in different studies (El-Sadr et al.,
293
2006; Mauck et al., 2001a; van der Straten et al., 2007) and phase I evaluation
294
(Mauck et al., 2001b). However, phase III study with a total of 1398 women enrolled
295
concluded that cellulose sulfate did not prevent HIV infection and may increase the
296
risk of HIV acquisition (Van Damme et al., 2008). The lack of consistence between
297
phase III and pre-phase III studies is still under discussion (Check, 2007; Neurath,
298
2008) and it is worth to re-evaluate the clinical results to solve related controversy.
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4.1.3 Cell regulation
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Cell growth and stem cell differentiation are regulated by various factors such growth
302
factors and extracellular matrices. The binding between sulfated cellulose and
303
fibroblast growth factors (FGF) have been studied in the literature. For example,
304
Weltrowski et al (Weltrowski et al., 2012) studied the mitogenic activity of cellulose
305
sulfate and its protective effect against proteolytic digestion of FGF-2. Their results
306
indicated that the mitogenic activity of cellulose sulfate was related to the substitution
307
degree and concentration of the polymer, which showed an increase of cell growth
308
with the increase substitution degree and concentration. Moreover, they found that the
309
mechanism on mitogenic activity was mainly related to a prolonged life-time of
310
FGF-2 by protection of FGF-2 against proteolytic digestion. Peschel et al. (Peschel et
311
al., 2010) investigated the cytotoxicity and motigenic activity of cellulose sulfate by
312
modulation of 3T3 fibroblast proliferation with or without FGF-2. Their results
313
showed that cellulose sulfate and their carboxyl and carboxymethyl derivatives were
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all non-toxic to 3T3 cells. Cellulose sulfate strongly promoted cell proliferation by
315
FGF-2 induction and this promotion was substitution degree related. Moreover,
316
cellulose sulfate were better than heparin in the absence of FGF-2. Meanwhile, no
317
significant promoting effects were found with carboxyl and carboxymethyl
318
derivatives of cellulose sulfate. In addition, the suppression of immunoglobulin E
319
expression by cellulose sulfate was studied (Morioke et al., 2012) and the application
320
of cellulose sulfate pairing with other polyelectrolytes on cell culture will be
321
discussed in the following section.
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Application Anticoagulation
Reference (Wang et al., 2007; Wang et al., 2010c)
Anticoagulant coatings Papillomavirus microbicide Vaginal microbicide
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Antiviral
Human Immunodeficiency Virus (HIV) treatment
ep te
Cell expression/proliferation regulation
(Gericke et al., 2011) (Christensen et al., 2001) (Simoes et al., 2002)
(El-Sadr et al., 2006; McGowan, 2006; Stone, 2002) (Mauck et al., 2001a; Mauck et al., 2008; van der Straten et al., 2007) (Aggarwal et al., 2013, 2014a; Morioke et al., 2012; Peschel et al., 2010)
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Cell regulation
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Contraception
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Table 3. Typical biological activities and applications of cellulose sulfate.
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4.2 Polyelectrolyte complexes
325
Polyelectrolyte complexes (PEC) usually refers to polymer systems formed by mixing
326
oppositely charged polyelectrolytes in solutions without covalent crosslinkers (Luo et
327
al., 2014). The formation process is based on the interaction between polyionic
328
polymers via electrostatic and dipole-dipole association, hydrogen bonds and
329
hydrophobic interactions. Therefore, the stability of PEC can be affected by various
330
factors, such as ionic strength and pH. Due to mild reaction conditions and wide
331
selection of polymers, PEC is often studied for drug delivery and biological
332
applications (Bertin, 2014; Müller, 2014).
333
Cellulose sulfate is a semi-synthesized polyanionic polymer that can form PEC with
334
various natural or synthetic polycations, such as chitosan and Poly-dimethyl-diallyl-
335
ammonium chloride. Moreover, the unique biological properties of cellulose sulfate
336
discussed in this review make it suitable and sometimes advantageous for some
337
high-demanding biotechnology applications, such as drug delivery and cell
338
immobilization. Table 4 summarized cellulose sulfate related PEC reported in the
339
literature and Figure 3 shows the chemical structures of the materials listed in Table 4.
340
Microencapsulation (Bhujbal et al., 2014) and layer-by-layer techniques (De Villiers
341
et al., 2011) are two of the most widely used approaches for cellulose sulfate PEC
342
preparation.
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21
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ip t
cr
Table 4. Typical cellulose sulfate related polyelectrolyte complexes (PEC) studied in the literature. Application
Preparation
Alginate/poly(methyle ne-co-guanidine) (PMCG)
Microbe/cell immobilization
Sodium alginate and cellulose sulfate (Briššová et al., 1997; Bučko et al., 2006; Bučko solutions were mixed and dropped into et al., 2005; Canaple et al., 2002; Lacík et al., 1997; Müller et al., 1999; Nahalka et al., 2008; CaCl2 and PMCG solution. Podskočová et al., 2005; Rehor et al., 2001; Renken et al., 2007; Vikartovská et al., 2007; Wang et al., 1997; Zhang et al., 2003, 2005b)
References
M
an
us
Chemical
for preparing (Lacík et al., 2001) sulfate-PMCG
d
A two-step process alginate-cellulose microcapsules.
ep te
A new device for microcapsule preparation (Ceausoglu et al., 2002) with controlled membrane and size.
Alginate and cellulose sulfate were mixed (Ponce et al., 2005) and gelled in calcium chloride solution.
chitosan
Cell culturing
Ac c
344
Drug delivery
Chitosan and cellulose sulfate films were (Aggarwal et al., 2013, 2014a) prepared via a layer-by-layer method.
Chitosan and cellulose sulfate films were (Xie et al., 2009) prepared via a layer-by-layer method. Chitosan and cellulose sulfate solutions (Wang et al., 2010a; Wang et al., 2009a; Zhu et were mixed. al., 2010)
22
Page 21 of 56
ip t
Poly-dimethyl-diallyl- Microbe/cell ammonium chloride immobilization (PDMDAAC)
Cellulose sulfate was dropped into water (Wu et al., 2014; Wu et al., 2013b) soluble chitosan solution and crosslinked with polyphosphate.
an
Drug delivery
PDMDAAC and cellulose sulfate were (Tan et al., 2011; Yao et al., 2006) deposited layer-by-layer on CaCO3 surface to obtain hollow microcapsules
M
Water soluble chitosan
us
cr
Cellulose sulfate was dropped into chitosan (Wu et al., 2013a; Zhang et al., 2013) solution and crosslinked with tripolyphosphate.
Ac c
ep te
d
Cellulose sulfate solution was dropped into (Dautzenberg et al., 1999a; Dautzenberg et al., 1999b; Fluri et al., 2008; Groot-Wassink et al., PDMDAAC solution. 1992; Liu et al., 2010; Mansfeld et al., 1995; Mansfeld et al., 1991; Merten et al., 1991; Samel et al., 2006; Son et al., 2004; Stadlbauer et al., 2006; Štefuca et al., 1991; Weber et al., 2006; Zeng et al., 2013a; Zeng et al., 2012; Zhang et al., 1999; Zhang et al., 2006) Starch was added in the system and later (Zhang et al., 2005a) removed by amylase to make macroporous capsules. Alginate was added in the system and later (Weber et al., 2004) removed by dissolution.
Carboxymethyl cellulose was added in the (Chen et al., 2005) cellulose sulfate/ PDMDAAC system to adjust microcapsule properties.
23
Page 22 of 56
Hexadecylpyridinium chloride (surfactant)
Membrane separation
ip t
Drug delivery； Poly(ethyleneimine) was mixed cellulose sulfate under stirring. Microbe/cell immobilization
with (Müller et al., 2012; Woltmann et al., 2014)
Layer-by-layer formation.
an
Dip-coating process.
us
cr
Poly(ethyleneimine)
(Schwarz et al., 2001)
Ac c
ep te
d
M
345
(Tamaddondar et al., 2014)
24
Page 23 of 56
ip t
346
Figure 3. Structures of chemicals used in the preparation of polyelectrolyte complexes
349
(PEC) with cellulose sulfate.
us
cr
347 348
an
350
4.2.1 Drug delivery
352
The efficiency of drug used by patients is often limited by delivery route, drug
353
instability, immunogenicity and physiological barriers. Therefore, tremendous efforts
354
have been made in developing drug delivery systems (Lu et al., 2014). Techniques
355
such as extrusion, emulsion and spray drying are often used in industry for the
356
production of drug particles encapsulated with various materials (Cook et al., 2012).
357
However, drugs like proteins have special preparation requirements and mild
358
operation conditions are often needed. PEC microencapsulation is a suitable approach
359
for such applications and literatures show that polysaccharides such as alginate,
360
chitosan and cellulose derivatives are the most common encapsulation agents due to
361
their biocompatibility, easy availability and unique biological properties (Cook et al.,
362
2012).
363
Research found that cellulose sulfate synthesized via homogeneous pathway is
364
preferred for microencapsulation, because good water solubility, high viscosity and
365
uniform sulfate group distribution are favored in PEC formation (Gericke et al.,
Ac ce
pt
ed
M
351
25
Page 24 of 56
2009a). Hartlig et al. (Hartlig et al., 2007) studied the effects of molecular weight of
367
cellulose sulfate on related PEC physicochemical properties. Sodium alginate and
368
poly(methylene-co-guanidine) (PMCG) were used as coupling polymers and the
369
results showed that polymers with similar low molecular weights resulted in PEC
370
dispersions with suitable physicochemical properties, while significantly different
371
molecular weight polymers lead to water insoluble aggregates. Müller and Keßler
372
(Müller
373
poly(ethyleneimine)/cellulose sulfate PEC films as controlled release matrices for
374
pamidronate, and the results showed that the drug release kinetics can be adjusted by
375
changing polymer mixing ratios. Supercritical fluid assisted atomization was also
376
applied in the preparation of cellulose sulfate, and spherical particles with narrow size
377
distribution and mean diameter from 0.3~3.0 μm can be obtained (Wang et al., 2010b).
378
In addition, chitosan as a polycation is often used with cellulose sulfate to form PEC
379
microcapsules. For example, 5-aminosalucylic acid and lactoferrin were encapsulated
380
individually with chitosan/cellulose sulfate/polyphosphate and good encapsulation
381
ratio and designed drug release profiles can be obtained (Wu et al., 2014; Wu et al.,
382
2013a; Wu et al., 2013b). Moreover, research showed the chitosan-cellulose sulfate
383
system can be used as a potential microbial-trigged colon-specific drug delivery
384
system (Wang et al., 2010a), as the PEC capsules formed by chitosan-cellulose sulfate
385
can only be degraded in the colon region after oral intake due to the rich of microbial
386
in human colon. For example, Figure 4 shows two blank capsules prepared by
387
chitosan-cellulose sulfate PEC and the actual size can be adjusted accordingly (Wang
388
et al., 2009a).
2012)
used
a
solution
casting
method
to
cr
al.,
prepare
Ac ce
pt
ed
M
an
us
et
ip t
366
389
26
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Figure 4. Blank capsules prepared with chitosan and cellulose sulfate. Adapted with
392
permission from reference (Wang et al., 2009a). Copyright (2009) American
393
Chemical Society.
cr
ip t
390 391
us
394
Layer-by-layer assembly is a more delicate technique for the encapsulation of drugs
396
and living organisms with cellulose sulfate (Aggarwal et al., 2014b). It can also be
397
used as surface coatings to modify various material surfaces (Baumann et al., 2003;
398
Müller et al., 1999). Multilayer PEC films or capsules are usually prepared by a
399
dipping-washing-dipping process, i.e. dip the template in one of the polymer solutions
400
for a certain time interval and then wash with distilled water and dip into the pairing
401
polymer solution. The whole process can be repeated until desired films are achieved.
402
Figure 5 is a schematic diagram shows the layered structure of chitosan and cellulose
403
sulfate (Xie et al., 2009). A detailed PEC forming mechanism was discussed which
404
shows the existence of competitive interaction between polyelectrolytes (Zhang et al.,
405
2013).
M
ed
pt
Ac ce
406
an
395
27
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ip t cr us
Figure 5. Schematic diagram of the layer-by-layer assembly with chitosan and
409
cellulose sulfate. Adapted with permission from reference (Xie et al., 2009).
410
Copyright (2009) American Chemical Society.
M
an
407 408
411 412
4.2.2 Microbe/cell immobilization
414
Cell immobilization or encapsulation is used to protect cells from external
415
environment and provide microenvironment for cell promotion, and controlling cell
416
viability, proliferation and release of therapeutic chemicals (Acarregui et al., 2012;
417
Orive et al., 2004; Orive et al., 2014). This technique is often considered for disease
418
treatments, which can be treated as advanced drug delivery systems with living cells
419
as individual bio-factories. Therefore, it is important that the encapsulating materials
420
do not have negative effects on cell growth, and it would be advantageous if the
421
materials used can facilitate drug producing of living cells. Cellulose sulfate has
422
unique biological activities and research has shown its potential applications in cell
423
regulation
424
immobilization/encapsulation. Cells such as antibody expressing mammalian cells
Ac ce
pt
ed
413
(Table
3).
Therefore,
it
is
a
promising
material
for
cell
28
Page 27 of 56
(Dautzenberg et al., 1999a), cellulase secreting mammalian sensor cells (Fluri et al.,
426
2008), jurkat cells(Kaiser et al., 2014; Werner et al., 2013), hybridoma cells (Shen et
427
al., 1993), yeast cells (Zhang et al., 1999), co-immobilized Yarrowia lipolytica cells
428
and invertase (Mansfeld et al., 1995), human mesenchymal stromal cells (Woltmann
429
et al., 2014), nocardia tartaricans cells (Bučko et al., 2006), Chinese hamster ovary
430
cells (Weber et al., 2004) and Choristoneura funiferana cells (Son et al., 2004) have
431
all been immobilized using cellulose sulfate and in vitro and in vivo studies were
432
performed. Some of the immobilization methods and materials are listed in Table 4.
433
Cellulose sulfate paired with poly-dimethyl-diallyl-ammonium chloride (PDMDAAC)
434
is the most popular PEC forming combination (Merten et al., 1991), which has
435
advantages of stable physiochemical properties, robust mechanical strength, good
436
biocompatibility and sharp cut-off membranes. A typical encapsulation process with
437
cellulose and PDMDAAC is illustrated in Figure 6.
Ac ce
pt
ed
M
an
us
cr
ip t
425
438 439
Figure 6. Schematic diagram of biological material encapsulation with polyelectrolyte
440
complexes formed by cellulose sulfate and poly-dimethyl-diallyl-ammonium chloride
441
(PDMDAAC). Adapted with permission from reference (Gericke et al., 2009a).
442
Copyright (2009) WILEY-VCH Verlag GmbH & Co.. 29
Page 28 of 56
A cytochrome P450 enzyme expressing and genetically modified allogeneic cells
444
were immobilized in cellulose sulfate capsules and its effects in pancreatic cancer
445
treatments were evaluation in a phase I/II trial (Löhr et al., 2001). The authors
446
concluded that higher survival rates might be obtainable with this strategy than
447
another cytotoxic agent. Cellulose sulfate related PEC has also been studied in
448
detailed for pancreatic islet cell transplantation for the treatment of diabetes mellitus
449
(Stadlbauer et al., 2006). Wang et al. (Wang et al., 1997) screened over a thousand
450
combinations of polyanions and polycations to search for new polymer candidates that
451
may suitable for encapsulating pancreatic islets. They found that the combination of
452
sodium alginate, cellulose sulfate, PMCG and some chloride salts was the most
453
promising. Stiegler et al. (Schaffellner et al., 2005; Stiegler et al., 2006) encapsulated
454
an insulin-producing cell line HIT-T15 with cellulose sulfate and PDMDAAC and
455
they demonstrated that cellulose sulfate is less immunogenic and more biocompatible
456
than other materials, and it did not influence cell growth and insulin production.
457
Essential nutrients and insulin can pass through the capsule membrane without
458
significant delay. Moreover, it was also found that freezing and thawing of the cells
459
immobilized in cellulose sulfate is possible.
460
In addition, the advantages of cellulose sulfate in cell encapsulation made it also a
461
promising candidate for microbe and enzyme immobilization. For example, bacteria
462
such as Klebsiella pneumoniae was encapsulated in cellulose sulfate-PDMDAAC
463
microcapsules for the production of 1,3-propanediol under both batch and continuous
464
modes (Zhao et al., 2006). The results showed that the biomass concentration was 2.6
465
times higher than that of free culturing in the microcapsules, and the substrate
466
tolerance and microbe activity were both increased. Lactate dehydrogenase was also
467
encapsulated in PEC matrices formed by dropping 2% w/w cellulose sulfate solution
Ac ce
pt
ed
M
an
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443
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into 2% w/w PDMDAAC solution (Štefuca et al., 1991). The results indicated that
469
this mild preparation condition was suitable for sensitive enzymes. Moreover, the
470
enzyme can move freely in PEC without leakage, while the substrates can easily
471
penetrate into the semipermeable microcapsules. Nahalka et al. (Nahalka et al., 2008)
472
studied the immobilization of D-amino acid oxidase in alginate/PMCG/cellulose
473
sulfate/CaCl2 systems and approximately 52% immobilization yield (expressed as the
474
fraction of original activity) was achieved. The enzyme entrapped was 720-fold more
475
stable than free enzymes, which indicates the potential industry value of this
476
technique. The same PEC system was used in encapsulation of glucose oxidase by
477
Vikartovská et al. (Vikartovská et al., 2007) and the results showed that the
478
encapsulated enzyme had higher thermostability and storage stability. The reusability
479
was also dramatically enhanced comparing to free enzymes. Zeng et al. (Zeng et al.,
480
2013a; Zeng et al., 2013b; Zeng et al., 2012) used the cellulose sulfate-PDMDAAC
481
system to immobilize microalgae Chlorella sp. for removing total nitrogen and
482
phosphate in wastewater. They found that the capsules prepared had good mechanical
483
stability, biocompatibility and high substrate tolerance. Moreover, the microalgae
484
immobilized had a robust morphology. Furthermore, the cellulose sulfate-PDMDAAC
485
system have also been applied in other microbe/enzyme investigations, such as
486
monascus purpureus for natural pigment production (Liu et al., 2010), invertase
487
(Mansfeld et al., 1991), bovine spermatozoa (Weber et al., 2006) and brevibacterium
488
flavum (Mei et al., 2005).
Ac ce
pt
ed
M
an
us
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468
489 490
4.2.3 Mass transfer in PEC
491
The physical, chemical and biological properties of encapsulating materials are the
492
basis in determining the applicability of living organism immobilization. However, 31
Page 30 of 56
mass transfer inside those semi-permeable matrices/membranes is often vital in
494
determining the success of such applications, as nutrients need to be transferred in and
495
products need to be transferred out. For example, the diffusion coefficient of glucose
496
in cellulose sulfate-PDMDAAC membranes was investigated with a diffusion model
497
and was found at ~ 2.12×10-11 m2/s (Shanjing et al., 1998). Groot-Wassink et al.
498
(Groot-Wassink et al., 1992) used cellulose sulfate and PDMDAAC for hybridoma
499
cell encapsulation and found that albumin and transferrin were not able to diffuse
500
through the membrane, although the system protected cells from damage. One
501
advantage of PEC systems is that the diffusion characteristics can be adjusted by
502
changing preparation procedures and processes. Zhang et al. (Zhang et al., 2003)
503
prepared a series of alginate/PMCG/cellulose sulfate systems with different polymer
504
concentrations and the diffusivity of nine solutes was measured to establish diffusion
505
mathematical models. The effect of molecular weight of PDMDAAC on the cellulose
506
sulfate-PDMDAAC membrane permeability was studied by Dautzenberg et al.
507
(Dautzenberg et al., 1999b). The results showed that a homogeneous membrane pore
508
structure and a sharp membrane cut-off of ~2 nm can be obtained with PDMDAAC
509
molecular weight > 10 kDa, which is enough for stable inclusion of enzymes with
510
molecular weight > 20 kDa. In order to prepare membranes with higher molecular
511
weight cut-off, macroporous cellulose sulfate-PDMDAAC membranes were prepared
512
by adding starch in the system which was later hydrolyzed by amylase (Zhang et al.,
513
2005a). The molecular cut-off of the membrane was 70 kDa for globular proteins that
514
was approximately five times larger than systems without starch. Moreover,
515
membranes prepared from cellulose sulfate related PEC were also applied in
516
membrane separation of gas mixtures (Schwarz et al., 2001; Tamaddondar et al.,
517
2014).
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493
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518
5. Conclusions and future perspectives
520
Cellulose sulfate is a cellulose derivative with unique biological properties. Its
521
bioactive and ionic nature made it a promising candidate for live organism
522
immobilization and even can be used as pharmaceutical active ingredients in disease
523
treatments. This review presented a summary of current research on cellulose sulfate.
524
The synthesis methods were discussed and the emphasis was focused on its
525
application in biotechnological fields. Nevertheless, cellulose sulfate is still a
526
lab-product without commercialization. The materials used in research are most
527
individually prepared. Therefore, results from different groups are not comparable and
528
sometimes lack consistence. It is important to develop affordable and robust synthesis
529
pathways to obtain products with reliable quality, and also explore techniques and
530
methods for clarifying their chemical structures. Furthermore, regioselective synthesis
531
of cellulose sulfate is vital in fulfilling high-demanding requirements from biological
532
industry.
pt
533
ed
M
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ip t
519
Acknowledgements
535
This work was financially supported by the National Natural Science Foundation of
536
China and the Doctoral Programs Foundation of Ministry of Education of China (No.
537
20110101130007).
538
Ac ce
534
539
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cellulose
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polyelectrolyte
complex
Ac ce
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M
an
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Oxyethylated cellulose sulfates. Polymer Science - Series B, 54(3-4), 175-182.
919
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Thompson, M., Chipato, T., Hammond, N., & Padian, N. (2007). A randomized
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controlled safety trial of the diaphragm and cellulose sulfate microbicide gel in
926
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hydrodynamic cavitation mixer. Chem. Eng. J., 159(1-3), 220-229.
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Preparation and anticoagulation activity of sodium cellulose sulfate. Int. J. Biol.
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of high-throughput-compatible protocols for microencapsulation, cryopreservation
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and release of bovine spermatozoa. J. Biotechnol., 123(2), 155-163.
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Fussenegger, M. (2004). CellMAC: A novel technology for encapsulation of
964
mammalian cells in cellulose sulfate/pDADMAC capsules assembled on a transient
965
alginate/Ca 2+ scaffold. J. Biotechnol., 114(3), 315-326.
966
Weltrowski, A., da Silva Almeida, M. L., Peschel, D., Zhang, K., Fischer, S., & Groth,
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T. (2012). Mitogenic Activity of Sulfated Chitosan and Cellulose Derivatives is
968
Related to Protection of FGF-2 from Proteolytic Cleavage. Macromol. Biosci., 12(6),
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740-750.
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Werner, M., Biss, K., Jérôme, V., Hilbrig, F., Freitag, R., Zambrano, K., Hübner, H.,
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Buchholz, R., Mahou, R., & Wandrey, C. (2013). Use of the mitochondria toxicity
972
assay for quantifying the viable cell density of microencapsulated jurkat cells.
973
Biotechnol. Prog., 29(4), 986-993.
974
Woltmann, B., Torger, B., Müller, M., & Hempel, U. (2014). Interaction between
975
immobilized polyelectrolyte complex nanoparticles and human mesenchymal stromal
976
cells. International Journal of Nanomedicine, 9(1), 2205-2215.
977
Wu, Q. X., Li, M. Z., & Yao, S. J. (2014). Performances of NaCS-WSC protein drug
978
microcapsules with different degree of substitution of NaCS using sodium
979
polyphosphate as cross-linking agent. Cellulose, 21(3), 1897-1908.
980
Wu, Q. X., & Yao, S. J. (2013a). Novel NaCS-CS-PPS microcapsules as a potential
981
enzyme-triggered release carrier for highly-loading 5-ASA. Colloids Surf. B.
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Biointerfaces, 109, 147-153.
983
Wu, Q. X., Zhang, Q. L., Lin, D. Q., & Yao, S. J. (2013b). Characterization of novel
984
lactoferrin loaded capsules prepared with polyelectrolyte complexes. Int. J. Pharm.,
985
455(1-2), 124-131.
986
Xie, Y. L., Wang, M. J., & Yao, S. J. (2009). Preparation and characterization of
987
biocompatible microcapsules of sodium cellulose sulfate/chitosan by means of
988
layer-by-layer self-assembly. Langmuir, 25(16), 8999-9005.
989
Yao, S. (2000). An improved process for the preparation of sodium cellulose sulphate.
990
Chem. Eng. J., 78(2-3), 199-204.
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Yao, S. J., Guan, Y. X., & Lin, D. Q. (2006). Mass transfer behavior of solutes in
992
NaCS-PDMDAAC capsules. Ind. Eng. Chem. Res., 45(5), 1811-1816.
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Yoshida, T. (2001). Synthesis of polysaccharides having specific biological activities.
994
Progress in Polymer Science (Oxford), 26(3), 379-441.
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Yoshida, T., Kang, B. W., Hattori, K., Mimura, T., Kaneko, Y., Nakashima, H.,
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Premanathan, M., Aragaki, R., Yamamoto, N., & Uryu, T. (2001). Anti-HIV activity
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of sulfonated arabinofuranan and xylofuranan. Carbohydr. Polym., 44(2), 141-150.
998
Zeng, X., Danquah, M. K., Halim, R., Yang, S., Chen, X. D., & Lu, Y. (2013a).
999
Comparative physicochemical analysis of suspended and immobilized cultivation of
ip t
995
Chlorella sp. J. Chem. Technol. Biotechnol., 88(2), 247-254.
1001
Zeng, X., Danquah, M. K., Potumarthi, R., Cao, J., Chen, X. D., & Lu, Y. (2013b).
1002
Characterization of sodium cellulose sulphate/poly-dimethyl-diallyl-ammonium
1003
chloride biological capsules for immobilized cultivation of microalgae. J. Chem.
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Technol. Biotechnol., 88(4), 599-605.
1005
Zeng, X., Danquah, M. K., Zheng, C., Potumarthi, R., Chen, X. D., & Lu, Y. (2012).
1006
NaCS-PDMDAAC immobilized autotrophic cultivation of Chlorella sp. for
1007
wastewater nitrogen and phosphate removal. Chem. Eng. J., 187, 185-192.
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Zhang, H., Mei, L., & Yao, S. (1999). Cultivation of encapsulated yeast cells in
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NaCS-PDMDAAC polyelectrolyte complexes. Chin. J. Biotechnol., 15(3), 165-170.
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Zhang, J., Guan, Y. X., Ji, Z., & Yao, S. J. (2006). Effects on membrane properties of
1011
NaCS-PDMDAAC capsules by adding inorganic salts. J. Membr. Sci., 277(1-2),
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270-276.
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Zhang, J., Yao, S. J., & Guan, Y. X. (2005a). Preparation of macroporous sodium
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cellulose sulphate/ poly(dimethyldiallylammonium chloride) capsules and their
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characteristics. J. Membr. Sci., 255(1-2), 89-98.
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Zhang, K., Brendler, E., & Fischer, S. (2010a). FT Raman investigation of sodium
1017
cellulose sulfate. Cellulose, 17(2), 427-435.
1018
Zhang, K., Brendler, E., Geissler, A., & Fischer, S. (2011a). Synthesis and
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spectroscopic analysis of cellulose sulfates with regulable total degrees of substitution
1020
and sulfation patterns via 13C NMR and FT Raman spectroscopy. Polymer, 52(1),
1021
26-32.
1022
Zhang, K., Peschel, D., Bäucker, E., Groth, T., & Fischer, S. (2011b). Synthesis and
1023
characterisation of cellulose sulfates regarding the degrees of substitution, degrees of
1024
polymerisation and morphology. Carbohydr. Polym., 83(4), 1659-1664.
1025
Zhang, K., Peschel, D., Brenaler, E., Groth, T., & Fischer, S. (2009). Synthesis and
1026
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1028
Synthesis of carboxyl cellulose sulfate with various contents of regioselectively
1029
introduced sulfate and carboxyl groups. Carbohydr. Polym., 82(1), 92-99.
1030
Zhang, L. Y., Yao, S. J., & Guan, Y. X. (2003). Diffusion characteristics of solutes
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with
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864-868.
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Zhang,
S.
J.,
&
1035
poly(methylene-co-guanidine)
on
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40(1), 189-193.
1038
Zhang, Q., Wu, Q., Lin, D., & Yao, S. (2013). Effect and mechanism of sodium
1039
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beads. Soft Matter, 9(43), 10354-10363.
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an
us
cr
ip t
1019
weight
pt
Y.,
Yao,
Ac ce
L.
molecular
ed
low
in
Guan,
sodium
Y. growth
X. in
alginate/cellulose
(2005b). an
Effects
of
alginate/cellulose
54
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Zhu, L., Qin, J., Yin, X., Ji, L., Lin, Q., & Qin, Z. (2014). Direct sulfation of bacterial
1044
cellulose with a ClSO3H/DMF complex and structure characterization of the sulfates.
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Polym. Adv. Technol., 25(2), 168-172.
1046
Zhu, L., & Yao, S. (2012). Preparation of sodium cellulose sulfate and determination
1047
of properties. Huaxue Fanying Gongcheng Yu Gongyi/Chemical Reaction Engineering
1048
and Technology, 28(2), 154-158.
1049
Zhu, L. Y., Lin, D. Q., & Yao, S. J. (2010). Biodegradation of polyelectrolyte complex
1050
films composed of chitosan and sodium cellulose sulfate as the controllable release
1051
carrier. Carbohydr. Polym., 82(2), 323-328.
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Zulkifli, F. H., Hussain, F. S. J., Rasad, M. S. B. A., & Mohd Yusoff, M. (2014).
1053
Nanostructured materials from hydroxyethyl cellulose for skin tissue engineering.
1054
Carbohydr. Polym., 114(0), 238-245.
1057 1058 1059 1060 1061 1062
cr
us
an
M
ed pt
1056
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1055
ip t
1043
1063 1064 1065 1066 55
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1067 1068 1069 1070
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1071 1072
cr
1073
Figure captions:
1075
Figure 1. Repeating units of some naturally occurring polysaccharide sulfates and
1076
cellulose sulfate.
an
us
1074
1077
Figure 2. Relationship of viscosity, degree of substitution and soluble part percentage
1079
of cellulose sulfate synthesis by heterogeneous pathways.
M
1078
ed
1080
Figure 3. Structures of chemicals used in the preparation of polyelectrolyte complexes
1082
(PEC) with cellulose sulfate.
pt
1081
Ac ce
1083 1084
Figure 4. Blank capsules prepared with chitosan and cellulose sulfate. Adapted with
1085
permission from reference (Wang et al., 2009a). Copyright (2009) American
1086
Chemical Society.
1087 1088
Figure 5. Schematic diagram of the layer-by-layer assembly with chitosan and
1089
cellulose sulfate. Adapted with permission from reference (Xie et al., 2009).
1090
Copyright (2009) American Chemical Society.
1091 1092
Figure 6. Schematic diagram of biological material encapsulation with polyelectrolyte 56
Page 55 of 56
complexes formed by cellulose sulfate and poly-dimethyl-diallyl-ammonium chloride
1094
(PDMDAAC). Adapted with permission from reference (Gericke et al., 2009a).
1095
Copyright (2009) WILEY-VCH Verlag GmbH & Co..
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S0144-8617(15)00548-2 http://dx.doi.org/doi:10.1016/j.carbpol.2015.06.041 CARP 10030
To appear in: Received date: Revised date: Accepted date:
30-4-2015 11-6-2015 12-6-2015
Please cite this article as: Zhang, Q., Lin, D., and Yao, S.,Review on biomedical and bioengineering applications of cellulose sulfate, Carbohydrate Polymers (2015), http://dx.doi.org/10.1016/j.carbpol.2015.06.041 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Highlights
2
The preparation and application of cellulose sulfate was reviewed.
4
Biomedical potentials of cellulose sulfate were emphasized.
5
Future perspectives on cellulose sulfate development were summarized.
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6
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Review on biomedical and bioengineering applications of cellulose sulfate
9 10 11 12
Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College
13
of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027,
14
China
ip t
Qilei Zhang, Dongqiang Lin, Shanjing Yao*
* Address for Correspondence:
17
Prof. Shan-Jing Yao
18
College of Chemical and Biological Engineering
19
Zhejiang University
20
Hangzhou, 310027
21
China
22
Tel: +86-571-87951982
23
Fax: +86-571-87951982
24
E-mail: [email protected]
26 27 28
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25
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Page 2 of 56
Abstract
35
Polysaccharide sulfates are naturally existing chemicals that show important
36
biological activities in living organisms. Cellulose sulfate is a semi-synthesized
37
polysaccharide sulfate with relatively simple chain structure and unique biological
38
properties, and its biological applications have been explored in research and clinical
39
trials. With the advance of cellulose derivatization and characterization, cellulose
40
sulfate molecules with tailored structures have been developed to fulfill individual
41
requirements. This review aims to provide a summary of recent development of
42
cellulose sulfate in biomedical applications. Its synthesis pathways were discussed
43
with structure-property relationship elucidated. The application of cellulose sulfate in
44
drug delivery and microbe/cell immobilization were summarized with emphasis given
45
on its polyelectrolyte complex formation processes.
M
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34
46
ed
47 48
Keywords: cellulose sulfate; cellulose sulfation; antiviral; polyelectrolyte complexes;
50
cell immobilization;
52 53 54
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51
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49
55 56 57 58 3
Page 3 of 56
1. Introduction
60
Polysaccharides are widely available biological polymers with remarkable structural
61
diversity. The unique backbone structure combined with good chemical amenability
62
further makes polysaccharides valuable resources. Currently, polysaccharides find
63
applications in almost every aspect of human life and with the functionality of
64
polysaccharide structures, it has become an important material in textile, medicine,
65
environmental protection, food and pharmaceutical industry (Lucia et al., 2012).
66
Cellulose is a simple polysaccharide with no branching or substituents, which is often
67
considered as the most abundant polymer in nature (Fox et al., 2011). It is massively
68
produced with relative low cost and shows wide applications in both industry and
69
academy (Glasser, 2004).
70
The hydroxyl groups of cellulose can fully or partially react with chemical agents to
71
obtain various derivatives with different degree of substitution (Habibi, 2014; Heinze
72
et al., 2012b), and a series of cellulose derivatives like esters (El Seoud et al., 2005)
73
and ethers (Nguyen et al., 2014) have been synthesized to meet specific requirements
74
from industry. Table 1 listed some typical cellulose derivatives currently available.
75
Due to structure similarity and biological origin, these esters and ethers have similar
76
applications in food and pharmaceutical industry. Most of these derivatives are also
77
mass produced.
78
Cellulose sulfate is a semi-synthesized cellulose derivative with relatively simple
79
chain structure and unique biological properties. Currently, it is still mainly produced
80
in lab-scale with limited commercial applications. Nevertheless, research has shown
81
that it can be applied as anticoagulant (Groth et al., 2001), antiviral (McCarthy, 2007),
82
contraceptive (Anderson et al., 2004), Human Immunodeficiency Virus (HIV)
83
microbicide (Stone, 2002), etc. These areas are hot spots for both academy and
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Page 4 of 56
industry, and the potential markets make cellulose sulfate unique among cellulose
85
derivatives. Similar biological activities of cellulose sulfate were originally found on
86
some naturally occurring polysaccharide sulfates (Heinze et al., 2010). For example,
87
Figure 1 shows the repeating units of heparan sulfate, chondroitin-6-sulfate and
88
dermatan sulfate which are three important polysaccharide sulfates found in living
89
organisms. Meanwhile, cellulose sulfate has certain advantages over natural
90
counterparts, such as defined chemical structure and easy separation/purification,
91
which make it suitable for industry scale production and application.
92
This review would like to provide a summary of research on cellulose sulfate, and
93
emphasis is given to its application in biotechnological and medical areas, especially
94
the application of cellulose sulfate as a polyanionic polymer to form polyelectrolyte
95
complex films or capsules with polycations. Material synthesis pathways are briefly
96
reviewed and a future perspective is included to discuss challenges and prospects of
97
cellulose sulfate.
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Application
Hydroxyethyl cellulose
-CH2CH2OH
Thickener；
cr
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an
Cellulose derivatives
us
Table 1. Examples of typical cellulose derivatives and their applications
pharmaceutical excipient -CH2CH(OH)CH3
Pharmaceutical
References
(Chronakis et al., 2002; Singh et al., 2003; Zulkifli et al., 2014) (Nguyen et al., 2011; Ogawa et al., 2014)
M
Hydroxypropyl cellulose
excipient；lubricant； thickener
Thickener
d
cellulose
-CH2CH2OH, -CH3
ep te
Hydroxyethyl methyl Hydroxypropyl methyl
-CH2CH(OH)CH3,
Pharmaceutical
cellulose
-CH3
excipient； emulsifier；
(Mischnick et al., 2013) (Jain et al., 2014; Khan et al., 2013; Lamberti et al., 2013; Siepmann et al., 2012)
thickener
Ethyl hydroxyethyl cellulose
-CH2CH2OH,
Ac c
98
Carboxymethyl cellulose
Methylcellulose
Emulsifier；
-CH2CH3
pharmaceutical excipient
-CH2COOH
Thickener； food
-CH3
(Calejo et al., 2013; Karlberg et al., 2005)
(Shlyapnikov et al., 2014; Tang et al., 2014)
additive； pharmaceutical excipient Thickener； emulsifier
(Lott et al., 2013; Noronha et al., 2014)
6
Page 6 of 56
ip t Emulsifier；
cr
-CH2CH3
(Cheu et al., 2001; Davidovich-Pinhas et al., 2015)
us
Ethylcellulose
-COCH3
Coating；fiber
Cellulose propionate
-COCH2CH3
Coating；film
(Bianchi et al., 1997)
Cellulose acetate propionate
-COCH2CH3,
Fiber； paint
(Huang et al., 2011) (Huang et al., 2011)
an
Cellulose acetate
M
pharmaceutical excipient
-COCH3 -COCH2CH2CH3, -COCH3 -NO2
Cellulose sulfate
-SO3H
Fiber；film；explosive
ep te
Cellulose nitrate
Fiber； paint
d
Cellulose acetate butyrate
(Caruso et al., 2000; Liu et al., 2002)
(Nartker et al., 2010)
Microbicide；
(Aggarwal et al., 2013; Neurath, 2008; Wang et al.,
anticoagulant；
1997)
pharmaceutical
99
Ac c
excipient； film
7
Page 7 of 56
ip t Figure 1. Repeating units of some naturally occurring polysaccharide sulfates and
101
cellulose sulfate.
us
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99 100
an
102
2. Cellulose sulfation: processing strategies
104
A series of synthetic procedures for the preparation of cellulose sulfate have been
105
investigated and methods for cellulose sulfation were recently reviewed by Heinze et
106
al. (Heinze et al., 2010; Heinze et al., 2012b). Therefore, detailed synthetic methods
107
and procedures will not be discussed here. Generally, three synthetic strategies have
108
been applied based on the solubility of substrates in reaction media. Table 2
109
summarized some typical synthetic methods reported in the literature.
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110
M
103
111
2.1 Heterogeneous sulfation
112
Cellulose is difficult to be dissolved in most solvents (Pinkert et al., 2009). Therefore,
113
if cellulose is used as a raw material, sulfation process unfolds usually as a
114
heterogeneous reaction. H2SO4 and propanol are the most used reactants for
115
heterogeneous sulfation of cellulose (Yao, 2000), and recently Chen et al. (Chen et al.,
116
2013) proposed a modified process that used ethanol to replace propanol to simplify
117
the synthetic procedure and reduce cost. In order to restrain chain cleavage catalyzed
118
by H2SO4, the reaction is usually performed below 0 oC. This restriction can be 8
Page 8 of 56
overcome by using SO3-complexes such as SO3-pyridine and SO3-DMF as the
120
sufation agents, and dimethylformamide (DMF) is usually used as the solvent to
121
suspend cellulose during reaction (Zhu et al., 2014). Since cellulose sulfate has to
122
reach certain substitution degree to be dissolved in DMF, this method often results in
123
products with high degree of substitution. The heterogeneous strategy uses simple raw
124
materials with flexible preparation procedures. However, one problem for
125
heterogeneous synthesis is non-uniform substitution. As cellulose is not fully
126
dissolved, substitution mainly happens at the amorphous parts of cellulose with the
127
crystalline part remain unreacted.
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119
an
128
2.2 Homogeneous sulfation
130
Homogeneous strategy can overcome this non-uniform substitution problem after
131
dissolving cellulose in certain solvents. Products from homogeneous synthesis usually
132
have even distribution, good solubility, and low chain degradation (Qin et al., 2014).
133
For example, N2O4/DMF was used for the synthesis of cellulose sulfate with
134
SO3-complexes as reactants (Wagenknecht et al., 1993). Cellulose nitrite is first
135
formed as an intermediate. It then reacted with SO3-complexes to obtain final
136
products with different degree of substitution. Moreover, cellulose sulfate synthesized
137
can be dissolved in water at very low degree of substitution (~0.3). However, N2O4 is
138
toxic which limits large scale production and also the application of the product in
139
biomedical areas (Gericke et al., 2009a). Meanwhile, ionic liquids have become
140
extremely popular in research (Rogers et al., 2003) and some are good dissolution
141
media for cellulose (Gericke et al., 2009b; Pinkert et al., 2009). Gericke et al.
142
(Gericke et al., 2009a) used 1-butyl-3-methylimidazolium chloride (BMIMCl),
143
1-ethyl-3-methylimidazolium acetate (EMIMAc) and 1-allyl-3methylimidazolium
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Page 9 of 56
chloride (AMIMCl) in homogeneous synthesis of cellulose sulfate. The results
145
showed that direct sulfation under completely homogeneous conditions was
146
applicable. The minimum degree of substitution required for water solubility of the
147
product was 0.25. It is worth to note that the cellulose-ionic liquid system usually has
148
high viscosity which sometimes makes mixing problematic. Therefore, cosolvents are
149
usually needed to reduce the system viscosity. Synthesis in ionic liquids seems a good
150
pathway to prepare cellulose sulfate, but the high cost of ionic liquids needs to be
151
aware when considering mass production.
us
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144
152
2.3 Quasi-homogeneous sulfation
154
In addition to homogeneous synthesis, cellulose derivatives with better solubility than
155
cellulose were used as reactants. Such strategies are referred as quasi-homogeneous
156
synthesis and the properties of cellulose sulfate prepared are usually dependent on
157
sulfation processes. Cellulose acetate, cellulose nitrite and trimethylsilyl cellulose
158
(TMS) are three typical derivatives used and the main problem of this strategy is the
159
complexity of reaction systems which need further effort for purification (Richter et
160
al., 2003).
161
The above discussed methods for cellulose sulfate synthesis are mainly for the
162
preparation of sodium salts. The development of sulfated cellulose has been further
163
explored in studying derivatives of cellulose sulfate (Heinze et al., 1999). For
164
example, methylated cellulose sulfate (Gohdes et al., 1997), carboxyl cellulose sulfate
165
(Zhang et al., 2010b), amino cellulose sulfate (Heinze et al., 2012a) and oxyethylated
166
cellulose sulfate (Udoratina et al., 2012) were synthesized with their biological
167
properties compared.
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Table 2. Typical pathways for cellulose sulfate synthesis. Typical chemical
Characteristics
Heterogeneous
H2SO4/propanol or
Low temperature is necessary; Non-uniformly
ethanol
substituted; Cheap raw material and good adjustability.
SO3-complex*/DMF
High degree of substitution; Non-uniformly
Cellulose acetate
Good
M
substituted. Quasi-homogeneous
us
Synthesis
an
170
reactant
solubility;
Need
further
Trimethylsilyl (TMS)
Regioselective
anhydride
solubility; Need large amount of chemicals.
N2O4/DMF
Ionic liquid
171
Negligible depolymerization.
SO3-complex/acetic
Ac c
Homogeneous
Degree of substitution is limited by TMS;
ep te
cellulose
d
purification.
synthesis;
Good
water
Good reactant and product solubility; High solvent toxicity. Good
reactant
and
product
solubility;
Uniform substitution; High viscosity.
Reference (Bhatt et al., 2008; Chen et al., 2013; Yao, 2000) (Zhu et al., 2014) (Zhang et al., 2009) (Richter et al., 2003) (Zhang et al., 2011a; Zhang et al., 2011b) (Wagenknecht et al., 1993) (Gericke et al., 2009a; Liebert et al., 2009; Tao et al., 2011)
*: SO3-complex can be SO3-DMF, SO3-pyridine, ClSO3H, etc.
12
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With the development of modern chemistry, fine manipulation of molecule becomes
173
possible and sometimes needed to obtained chemicals with specific properties.
174
Reaction conditions are milder when cellulose is fully dissolved that breaks extensive
175
H-bonds, which make it possible for regioselective and regiospecific synthesis of
176
cellulose derivatives (Fox et al., 2011). The regioselective synthesis of cellulose
177
sulfate has been reviewed (Baumann et al., 2003; Fox et al., 2011; Klemm et al.,
178
1997), and heterogeneous, quasi-homogeneous and homogeneous strategies have all
179
been applied with various reactants and solvent systems. However, many researchers
180
only use 1H and 13C NMR spectra data to support the regioselective synthesis, which
181
are not always convincing. Therefore, it is also important to develop a comprehensive
182
characterizing package for such research (Gohdes et al., 1998).
183
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172
3. Structure-property relationship
185
Like many other polymers, the physical, chemical and biological properties of
186
cellulose sulfate, such as water solubility, chemical reaction and biological activity are
187
largely dependent on the molecular weight, the degree and distribution of substitution
188
along polymer chains (Heinze et al., 2010). It has been noted that the quantification of
189
cellulose sulfation remains challenging(Gu et al., 2013). Several characterizing
190
techniques have been applied in structure study. For example, Raman and infrared
191
spectroscopy were used to measure substitution degree (Petropavlovskii et al., 1971;
192
Zhang et al., 2010a). The correlation between certain Raman vibration signals with
193
total degree of substitution was built and the correlation results were compared with
194
13
195
which indicated that Raman spectroscopy can be a potential rapid method for
196
quantifying degree of substitution (Zhang et al., 2011a). Zhu and Yao (Zhu et al.,
Ac ce
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184
C nuclear magnetic resonance (NMR) spectroscopy and elemental analysis results,
13
Page 12 of 56
2012) compared polyelectrolyte titration, BaSO4 turbidimetry and elemental analysis
198
methods in the measurement of substitution degree. They found that BaSO4
199
turbidimetry and elemental analysis can provide similar results, but the polyelectrolyte
200
titration lacked consistency. Moreover, the distribution of sulfate group is an
201
important physical factor that can affect water solubility of cellulose sulfate. Gohdes
202
and Mischnick (Gohdes et al., 1998) used a series of methods including
203
permethylation, desulfation, deuteromethylation, random cleavage, remethylation, and
204
fast-atom bombardment mass spectrum to determine the substitution pattern of
205
cellulose sulfate by analysis of degraded samples. Cellulose sulfate prepared from
206
seven different sulfation processes were compared. Their work provided detailed
207
results about positions of sulfated groups on cellulose chains. Two-dimensional 1H
208
and 13C NMR spectroscopy (Kowsaka et al., 1991) and mass spectrometry (Mischnick
209
et al., 1999) were also applied in the determination of substitution distribution.
210
Moreover, the molecular weight of cellulose sulfate can be measured by low angle
211
laser light scattering (LALLS) and gel permeation chromatography (GPC) (Wang et
212
al., 2009b; Zhu et al., 2012), while LALLS has advantages of measurement without
213
standard polymer samples. Other properties of cellulose sulfate such as liquid crystal
214
formation were also discussed in literature studied by differential scanning
215
calorimetry (DSC) and X-ray diffractometry (Hatakeyama et al., 1995; Onishi et al.,
216
2009).
217
The performance of polymer materials in various applications is usually closely
218
related to their structures. Table 2 shows that the structure properties are most likely
219
determined by the reaction pathways. Heterogeneous synthesis usually results in the
220
formation of non-uniform substitution distribution, which is due to the solubility
221
difference of amorphous and crystalline parts of cellulose in solvents. Meanwhile, the
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degree of substitution is affected by reaction type and time. For examples, the
223
relationship between degree of substitution, percentage of water soluble parts and
224
viscosity was studied under heterogeneous synthesis with H2SO4/propanol mixtures
225
and the results can be schematically depicted (see Figure 2) (Heinze et al., 2012b). It
226
seems reasonable that with the increase of soluble part percentage and degree of
227
substitution, the viscosity of cellulose sulfate decreases.
228 229
Figure 2. Relationship of viscosity, degree of substitution and soluble part percentage
230
of cellulose sulfate synthesis by heterogeneous pathways.
pt
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ed
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222
232
The effect of sulfate groups on the properties of cellulose sulfate has been widely
233
studied, especially on sulfated nanocrystalline cellulose. For example, Voronova et al.
234
(Voronova et al., 2013) prepared films composed of nanocrystalline cellulose sulfate
235
and the relationship between film property and sulfate group contents was studied.
236
The results showed that both surface roughness and water adsorption ability enhanced
237
with the increase of sulfate group. Jiang et al. (Jiang et al., 2013) used sulfated
238
cellulose as substrates for cellulase to study the effects of sulfate group on cellulase 15
Page 14 of 56
adsorption and enzymatic hydrolysis. They found that the surface accessibility was
240
similar with different sulfate group density, but the binding domain decreased. An
241
inhibitory effect of sulfate group in enzymatic hydrolysis was discussed. Moreover,
242
the effects of sulfate groups on the thermal degradation of cellulose was studied (Lin
243
et al., 2014; Roman et al., 2004). The results showed that the degradation temperature
244
was significantly decreased with the sulfation of cellulose, and the sulfate group
245
showed a catalytic effect on cellulose thermal degradation. Lokanathan et al.
246
(Lokanathan et al., 2013) used cellulose nanocrystals to assist the synthesis of silver
247
nanoparticles. The results showed that cellulose after sulfation can stabilize silver
248
nanoparticles formation and the decrease of substitution resulted in narrower
249
nanoparticle size distribution. Moreover, Cellulose sulfate with high degree of
250
substitution has shown potential application as Microbicides (Anderson et al., 2002;
251
Yoshida, 2001; Yoshida et al., 2001).
ed
252
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239
4. Biomedical applications of cellulose sulfate
254
4.1 Biological activity
255
Polysaccharide sulfates in living organisms were early found playing certain roles in
256
their biological activities, such as antiviral and blood coagulation(Ghosh et al., 2009;
257
Kindness et al., 1980). Currently, various semi-synthesized polysaccharide sulfates
258
have been developed and similar biological behaviors are also found from these
259
materials, such as chitosan sulfate, dextran sulfate and cellulose sulfate (Groth et al.,
260
2001). This review is focused on the application of cellulose sulfate with some typical
261
biological activities and related applications summarized in Table 3.
Ac ce
pt
253
262 263
4.1.1 Anticoagulation 16
Page 15 of 56
Natural heparin is a widely used anticoagulant in clinical application but shows
265
certain side effects (Han et al., 2005). Therefore, development of alternatives like
266
cellulose sulfate is important. Moreover, cellulose sulfate has well defined structure
267
and lack of branches on polymer chains, which is good for quality control and
268
structure-activity research. Wang et al. (Wang et al., 2007) found that cellulose sulfate
269
showed higher anticoagulation activity than heparin under their experimental
270
conditions, and in vivo studies revealed that the anticoagulation activity of cellulose
271
sulfate was achieved by accelerating the inhabitation of antithrombin III on
272
coagulation factors in plasma. Similar anticoagulation mechanism was discussed by
273
Grombe et al. (Grombe et al., 2007). The effects of molecular weight and sulfate
274
group distribution on anticoagulation were also investigated (Wang et al., 2005; Wang
275
et al., 2010c). Although it was revealed that molecular weight was important in the
276
anticoagulation application, their in vitro and in vivo results seem controversial and
277
further research may be necessary in studying the structure-activity relationship.
cr
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264
4.1.2 Antiviral: HIV treatments
280
Antiviral has a large market in pharmaceutical industry and is a major focus for
281
biotech companies (McCarthy, 2007). Among newly developed antiviral substances in
282
recent years, sulfated polysaccharides are often highlighted. Some aspects of their
283
antiviral activity have also been elucidated, which becomes clear that the charge
284
density and chain length are not the only contributors in their antiviral performance
285
(Ghosh et al., 2009). Cellulose sulfate is one of the most reported sulfated
286
polysaccharides in antiviral investigation, which may mainly be attributed to a
287
commercial drug candidate named UshercellTM. It is a high molecular weight form of
288
cellulose sulfate developed by Polydex (Canda) and was found active against human
Ac ce
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279
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immunodeficiency virus (HIV), herpes simplex virus (HSV), Neisseria gonorrhoeae,
290
Chlamydia trachomatis, papillomaviruses and gardnerella vaginalis (Anderson et al.,
291
2004). UshercellTM also shows contraceptive in preclinical evaluations (Anderson et
292
al., 2002) and it has excellent safety performance in different studies (El-Sadr et al.,
293
2006; Mauck et al., 2001a; van der Straten et al., 2007) and phase I evaluation
294
(Mauck et al., 2001b). However, phase III study with a total of 1398 women enrolled
295
concluded that cellulose sulfate did not prevent HIV infection and may increase the
296
risk of HIV acquisition (Van Damme et al., 2008). The lack of consistence between
297
phase III and pre-phase III studies is still under discussion (Check, 2007; Neurath,
298
2008) and it is worth to re-evaluate the clinical results to solve related controversy.
an
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289
299
4.1.3 Cell regulation
301
Cell growth and stem cell differentiation are regulated by various factors such growth
302
factors and extracellular matrices. The binding between sulfated cellulose and
303
fibroblast growth factors (FGF) have been studied in the literature. For example,
304
Weltrowski et al (Weltrowski et al., 2012) studied the mitogenic activity of cellulose
305
sulfate and its protective effect against proteolytic digestion of FGF-2. Their results
306
indicated that the mitogenic activity of cellulose sulfate was related to the substitution
307
degree and concentration of the polymer, which showed an increase of cell growth
308
with the increase substitution degree and concentration. Moreover, they found that the
309
mechanism on mitogenic activity was mainly related to a prolonged life-time of
310
FGF-2 by protection of FGF-2 against proteolytic digestion. Peschel et al. (Peschel et
311
al., 2010) investigated the cytotoxicity and motigenic activity of cellulose sulfate by
312
modulation of 3T3 fibroblast proliferation with or without FGF-2. Their results
313
showed that cellulose sulfate and their carboxyl and carboxymethyl derivatives were
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Page 17 of 56
all non-toxic to 3T3 cells. Cellulose sulfate strongly promoted cell proliferation by
315
FGF-2 induction and this promotion was substitution degree related. Moreover,
316
cellulose sulfate were better than heparin in the absence of FGF-2. Meanwhile, no
317
significant promoting effects were found with carboxyl and carboxymethyl
318
derivatives of cellulose sulfate. In addition, the suppression of immunoglobulin E
319
expression by cellulose sulfate was studied (Morioke et al., 2012) and the application
320
of cellulose sulfate pairing with other polyelectrolytes on cell culture will be
321
discussed in the following section.
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Page 18 of 56
Application Anticoagulation
Reference (Wang et al., 2007; Wang et al., 2010c)
Anticoagulant coatings Papillomavirus microbicide Vaginal microbicide
M
Antiviral
Human Immunodeficiency Virus (HIV) treatment
ep te
Cell expression/proliferation regulation
(Gericke et al., 2011) (Christensen et al., 2001) (Simoes et al., 2002)
(El-Sadr et al., 2006; McGowan, 2006; Stone, 2002) (Mauck et al., 2001a; Mauck et al., 2008; van der Straten et al., 2007) (Aggarwal et al., 2013, 2014a; Morioke et al., 2012; Peschel et al., 2010)
Ac c
Cell regulation
d
Contraception
323
cr
ip t Biological activity Anticoagulation
us
Table 3. Typical biological activities and applications of cellulose sulfate.
an
322
20
Page 19 of 56
4.2 Polyelectrolyte complexes
325
Polyelectrolyte complexes (PEC) usually refers to polymer systems formed by mixing
326
oppositely charged polyelectrolytes in solutions without covalent crosslinkers (Luo et
327
al., 2014). The formation process is based on the interaction between polyionic
328
polymers via electrostatic and dipole-dipole association, hydrogen bonds and
329
hydrophobic interactions. Therefore, the stability of PEC can be affected by various
330
factors, such as ionic strength and pH. Due to mild reaction conditions and wide
331
selection of polymers, PEC is often studied for drug delivery and biological
332
applications (Bertin, 2014; Müller, 2014).
333
Cellulose sulfate is a semi-synthesized polyanionic polymer that can form PEC with
334
various natural or synthetic polycations, such as chitosan and Poly-dimethyl-diallyl-
335
ammonium chloride. Moreover, the unique biological properties of cellulose sulfate
336
discussed in this review make it suitable and sometimes advantageous for some
337
high-demanding biotechnology applications, such as drug delivery and cell
338
immobilization. Table 4 summarized cellulose sulfate related PEC reported in the
339
literature and Figure 3 shows the chemical structures of the materials listed in Table 4.
340
Microencapsulation (Bhujbal et al., 2014) and layer-by-layer techniques (De Villiers
341
et al., 2011) are two of the most widely used approaches for cellulose sulfate PEC
342
preparation.
cr
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324
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Table 4. Typical cellulose sulfate related polyelectrolyte complexes (PEC) studied in the literature. Application
Preparation
Alginate/poly(methyle ne-co-guanidine) (PMCG)
Microbe/cell immobilization
Sodium alginate and cellulose sulfate (Briššová et al., 1997; Bučko et al., 2006; Bučko solutions were mixed and dropped into et al., 2005; Canaple et al., 2002; Lacík et al., 1997; Müller et al., 1999; Nahalka et al., 2008; CaCl2 and PMCG solution. Podskočová et al., 2005; Rehor et al., 2001; Renken et al., 2007; Vikartovská et al., 2007; Wang et al., 1997; Zhang et al., 2003, 2005b)
References
M
an
us
Chemical
for preparing (Lacík et al., 2001) sulfate-PMCG
d
A two-step process alginate-cellulose microcapsules.
ep te
A new device for microcapsule preparation (Ceausoglu et al., 2002) with controlled membrane and size.
Alginate and cellulose sulfate were mixed (Ponce et al., 2005) and gelled in calcium chloride solution.
chitosan
Cell culturing
Ac c
344
Drug delivery
Chitosan and cellulose sulfate films were (Aggarwal et al., 2013, 2014a) prepared via a layer-by-layer method.
Chitosan and cellulose sulfate films were (Xie et al., 2009) prepared via a layer-by-layer method. Chitosan and cellulose sulfate solutions (Wang et al., 2010a; Wang et al., 2009a; Zhu et were mixed. al., 2010)
22
Page 21 of 56
ip t
Poly-dimethyl-diallyl- Microbe/cell ammonium chloride immobilization (PDMDAAC)
Cellulose sulfate was dropped into water (Wu et al., 2014; Wu et al., 2013b) soluble chitosan solution and crosslinked with polyphosphate.
an
Drug delivery
PDMDAAC and cellulose sulfate were (Tan et al., 2011; Yao et al., 2006) deposited layer-by-layer on CaCO3 surface to obtain hollow microcapsules
M
Water soluble chitosan
us
cr
Cellulose sulfate was dropped into chitosan (Wu et al., 2013a; Zhang et al., 2013) solution and crosslinked with tripolyphosphate.
Ac c
ep te
d
Cellulose sulfate solution was dropped into (Dautzenberg et al., 1999a; Dautzenberg et al., 1999b; Fluri et al., 2008; Groot-Wassink et al., PDMDAAC solution. 1992; Liu et al., 2010; Mansfeld et al., 1995; Mansfeld et al., 1991; Merten et al., 1991; Samel et al., 2006; Son et al., 2004; Stadlbauer et al., 2006; Štefuca et al., 1991; Weber et al., 2006; Zeng et al., 2013a; Zeng et al., 2012; Zhang et al., 1999; Zhang et al., 2006) Starch was added in the system and later (Zhang et al., 2005a) removed by amylase to make macroporous capsules. Alginate was added in the system and later (Weber et al., 2004) removed by dissolution.
Carboxymethyl cellulose was added in the (Chen et al., 2005) cellulose sulfate/ PDMDAAC system to adjust microcapsule properties.
23
Page 22 of 56
Hexadecylpyridinium chloride (surfactant)
Membrane separation
ip t
Drug delivery； Poly(ethyleneimine) was mixed cellulose sulfate under stirring. Microbe/cell immobilization
with (Müller et al., 2012; Woltmann et al., 2014)
Layer-by-layer formation.
an
Dip-coating process.
us
cr
Poly(ethyleneimine)
(Schwarz et al., 2001)
Ac c
ep te
d
M
345
(Tamaddondar et al., 2014)
24
Page 23 of 56
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346
Figure 3. Structures of chemicals used in the preparation of polyelectrolyte complexes
349
(PEC) with cellulose sulfate.
us
cr
347 348
an
350
4.2.1 Drug delivery
352
The efficiency of drug used by patients is often limited by delivery route, drug
353
instability, immunogenicity and physiological barriers. Therefore, tremendous efforts
354
have been made in developing drug delivery systems (Lu et al., 2014). Techniques
355
such as extrusion, emulsion and spray drying are often used in industry for the
356
production of drug particles encapsulated with various materials (Cook et al., 2012).
357
However, drugs like proteins have special preparation requirements and mild
358
operation conditions are often needed. PEC microencapsulation is a suitable approach
359
for such applications and literatures show that polysaccharides such as alginate,
360
chitosan and cellulose derivatives are the most common encapsulation agents due to
361
their biocompatibility, easy availability and unique biological properties (Cook et al.,
362
2012).
363
Research found that cellulose sulfate synthesized via homogeneous pathway is
364
preferred for microencapsulation, because good water solubility, high viscosity and
365
uniform sulfate group distribution are favored in PEC formation (Gericke et al.,
Ac ce
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351
25
Page 24 of 56
2009a). Hartlig et al. (Hartlig et al., 2007) studied the effects of molecular weight of
367
cellulose sulfate on related PEC physicochemical properties. Sodium alginate and
368
poly(methylene-co-guanidine) (PMCG) were used as coupling polymers and the
369
results showed that polymers with similar low molecular weights resulted in PEC
370
dispersions with suitable physicochemical properties, while significantly different
371
molecular weight polymers lead to water insoluble aggregates. Müller and Keßler
372
(Müller
373
poly(ethyleneimine)/cellulose sulfate PEC films as controlled release matrices for
374
pamidronate, and the results showed that the drug release kinetics can be adjusted by
375
changing polymer mixing ratios. Supercritical fluid assisted atomization was also
376
applied in the preparation of cellulose sulfate, and spherical particles with narrow size
377
distribution and mean diameter from 0.3~3.0 μm can be obtained (Wang et al., 2010b).
378
In addition, chitosan as a polycation is often used with cellulose sulfate to form PEC
379
microcapsules. For example, 5-aminosalucylic acid and lactoferrin were encapsulated
380
individually with chitosan/cellulose sulfate/polyphosphate and good encapsulation
381
ratio and designed drug release profiles can be obtained (Wu et al., 2014; Wu et al.,
382
2013a; Wu et al., 2013b). Moreover, research showed the chitosan-cellulose sulfate
383
system can be used as a potential microbial-trigged colon-specific drug delivery
384
system (Wang et al., 2010a), as the PEC capsules formed by chitosan-cellulose sulfate
385
can only be degraded in the colon region after oral intake due to the rich of microbial
386
in human colon. For example, Figure 4 shows two blank capsules prepared by
387
chitosan-cellulose sulfate PEC and the actual size can be adjusted accordingly (Wang
388
et al., 2009a).
2012)
used
a
solution
casting
method
to
cr
al.,
prepare
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366
389
26
Page 25 of 56
Figure 4. Blank capsules prepared with chitosan and cellulose sulfate. Adapted with
392
permission from reference (Wang et al., 2009a). Copyright (2009) American
393
Chemical Society.
cr
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390 391
us
394
Layer-by-layer assembly is a more delicate technique for the encapsulation of drugs
396
and living organisms with cellulose sulfate (Aggarwal et al., 2014b). It can also be
397
used as surface coatings to modify various material surfaces (Baumann et al., 2003;
398
Müller et al., 1999). Multilayer PEC films or capsules are usually prepared by a
399
dipping-washing-dipping process, i.e. dip the template in one of the polymer solutions
400
for a certain time interval and then wash with distilled water and dip into the pairing
401
polymer solution. The whole process can be repeated until desired films are achieved.
402
Figure 5 is a schematic diagram shows the layered structure of chitosan and cellulose
403
sulfate (Xie et al., 2009). A detailed PEC forming mechanism was discussed which
404
shows the existence of competitive interaction between polyelectrolytes (Zhang et al.,
405
2013).
M
ed
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406
an
395
27
Page 26 of 56
ip t cr us
Figure 5. Schematic diagram of the layer-by-layer assembly with chitosan and
409
cellulose sulfate. Adapted with permission from reference (Xie et al., 2009).
410
Copyright (2009) American Chemical Society.
M
an
407 408
411 412
4.2.2 Microbe/cell immobilization
414
Cell immobilization or encapsulation is used to protect cells from external
415
environment and provide microenvironment for cell promotion, and controlling cell
416
viability, proliferation and release of therapeutic chemicals (Acarregui et al., 2012;
417
Orive et al., 2004; Orive et al., 2014). This technique is often considered for disease
418
treatments, which can be treated as advanced drug delivery systems with living cells
419
as individual bio-factories. Therefore, it is important that the encapsulating materials
420
do not have negative effects on cell growth, and it would be advantageous if the
421
materials used can facilitate drug producing of living cells. Cellulose sulfate has
422
unique biological activities and research has shown its potential applications in cell
423
regulation
424
immobilization/encapsulation. Cells such as antibody expressing mammalian cells
Ac ce
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ed
413
(Table
3).
Therefore,
it
is
a
promising
material
for
cell
28
Page 27 of 56
(Dautzenberg et al., 1999a), cellulase secreting mammalian sensor cells (Fluri et al.,
426
2008), jurkat cells(Kaiser et al., 2014; Werner et al., 2013), hybridoma cells (Shen et
427
al., 1993), yeast cells (Zhang et al., 1999), co-immobilized Yarrowia lipolytica cells
428
and invertase (Mansfeld et al., 1995), human mesenchymal stromal cells (Woltmann
429
et al., 2014), nocardia tartaricans cells (Bučko et al., 2006), Chinese hamster ovary
430
cells (Weber et al., 2004) and Choristoneura funiferana cells (Son et al., 2004) have
431
all been immobilized using cellulose sulfate and in vitro and in vivo studies were
432
performed. Some of the immobilization methods and materials are listed in Table 4.
433
Cellulose sulfate paired with poly-dimethyl-diallyl-ammonium chloride (PDMDAAC)
434
is the most popular PEC forming combination (Merten et al., 1991), which has
435
advantages of stable physiochemical properties, robust mechanical strength, good
436
biocompatibility and sharp cut-off membranes. A typical encapsulation process with
437
cellulose and PDMDAAC is illustrated in Figure 6.
Ac ce
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425
438 439
Figure 6. Schematic diagram of biological material encapsulation with polyelectrolyte
440
complexes formed by cellulose sulfate and poly-dimethyl-diallyl-ammonium chloride
441
(PDMDAAC). Adapted with permission from reference (Gericke et al., 2009a).
442
Copyright (2009) WILEY-VCH Verlag GmbH & Co.. 29
Page 28 of 56
A cytochrome P450 enzyme expressing and genetically modified allogeneic cells
444
were immobilized in cellulose sulfate capsules and its effects in pancreatic cancer
445
treatments were evaluation in a phase I/II trial (Löhr et al., 2001). The authors
446
concluded that higher survival rates might be obtainable with this strategy than
447
another cytotoxic agent. Cellulose sulfate related PEC has also been studied in
448
detailed for pancreatic islet cell transplantation for the treatment of diabetes mellitus
449
(Stadlbauer et al., 2006). Wang et al. (Wang et al., 1997) screened over a thousand
450
combinations of polyanions and polycations to search for new polymer candidates that
451
may suitable for encapsulating pancreatic islets. They found that the combination of
452
sodium alginate, cellulose sulfate, PMCG and some chloride salts was the most
453
promising. Stiegler et al. (Schaffellner et al., 2005; Stiegler et al., 2006) encapsulated
454
an insulin-producing cell line HIT-T15 with cellulose sulfate and PDMDAAC and
455
they demonstrated that cellulose sulfate is less immunogenic and more biocompatible
456
than other materials, and it did not influence cell growth and insulin production.
457
Essential nutrients and insulin can pass through the capsule membrane without
458
significant delay. Moreover, it was also found that freezing and thawing of the cells
459
immobilized in cellulose sulfate is possible.
460
In addition, the advantages of cellulose sulfate in cell encapsulation made it also a
461
promising candidate for microbe and enzyme immobilization. For example, bacteria
462
such as Klebsiella pneumoniae was encapsulated in cellulose sulfate-PDMDAAC
463
microcapsules for the production of 1,3-propanediol under both batch and continuous
464
modes (Zhao et al., 2006). The results showed that the biomass concentration was 2.6
465
times higher than that of free culturing in the microcapsules, and the substrate
466
tolerance and microbe activity were both increased. Lactate dehydrogenase was also
467
encapsulated in PEC matrices formed by dropping 2% w/w cellulose sulfate solution
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into 2% w/w PDMDAAC solution (Štefuca et al., 1991). The results indicated that
469
this mild preparation condition was suitable for sensitive enzymes. Moreover, the
470
enzyme can move freely in PEC without leakage, while the substrates can easily
471
penetrate into the semipermeable microcapsules. Nahalka et al. (Nahalka et al., 2008)
472
studied the immobilization of D-amino acid oxidase in alginate/PMCG/cellulose
473
sulfate/CaCl2 systems and approximately 52% immobilization yield (expressed as the
474
fraction of original activity) was achieved. The enzyme entrapped was 720-fold more
475
stable than free enzymes, which indicates the potential industry value of this
476
technique. The same PEC system was used in encapsulation of glucose oxidase by
477
Vikartovská et al. (Vikartovská et al., 2007) and the results showed that the
478
encapsulated enzyme had higher thermostability and storage stability. The reusability
479
was also dramatically enhanced comparing to free enzymes. Zeng et al. (Zeng et al.,
480
2013a; Zeng et al., 2013b; Zeng et al., 2012) used the cellulose sulfate-PDMDAAC
481
system to immobilize microalgae Chlorella sp. for removing total nitrogen and
482
phosphate in wastewater. They found that the capsules prepared had good mechanical
483
stability, biocompatibility and high substrate tolerance. Moreover, the microalgae
484
immobilized had a robust morphology. Furthermore, the cellulose sulfate-PDMDAAC
485
system have also been applied in other microbe/enzyme investigations, such as
486
monascus purpureus for natural pigment production (Liu et al., 2010), invertase
487
(Mansfeld et al., 1991), bovine spermatozoa (Weber et al., 2006) and brevibacterium
488
flavum (Mei et al., 2005).
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489 490
4.2.3 Mass transfer in PEC
491
The physical, chemical and biological properties of encapsulating materials are the
492
basis in determining the applicability of living organism immobilization. However, 31
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mass transfer inside those semi-permeable matrices/membranes is often vital in
494
determining the success of such applications, as nutrients need to be transferred in and
495
products need to be transferred out. For example, the diffusion coefficient of glucose
496
in cellulose sulfate-PDMDAAC membranes was investigated with a diffusion model
497
and was found at ~ 2.12×10-11 m2/s (Shanjing et al., 1998). Groot-Wassink et al.
498
(Groot-Wassink et al., 1992) used cellulose sulfate and PDMDAAC for hybridoma
499
cell encapsulation and found that albumin and transferrin were not able to diffuse
500
through the membrane, although the system protected cells from damage. One
501
advantage of PEC systems is that the diffusion characteristics can be adjusted by
502
changing preparation procedures and processes. Zhang et al. (Zhang et al., 2003)
503
prepared a series of alginate/PMCG/cellulose sulfate systems with different polymer
504
concentrations and the diffusivity of nine solutes was measured to establish diffusion
505
mathematical models. The effect of molecular weight of PDMDAAC on the cellulose
506
sulfate-PDMDAAC membrane permeability was studied by Dautzenberg et al.
507
(Dautzenberg et al., 1999b). The results showed that a homogeneous membrane pore
508
structure and a sharp membrane cut-off of ~2 nm can be obtained with PDMDAAC
509
molecular weight > 10 kDa, which is enough for stable inclusion of enzymes with
510
molecular weight > 20 kDa. In order to prepare membranes with higher molecular
511
weight cut-off, macroporous cellulose sulfate-PDMDAAC membranes were prepared
512
by adding starch in the system which was later hydrolyzed by amylase (Zhang et al.,
513
2005a). The molecular cut-off of the membrane was 70 kDa for globular proteins that
514
was approximately five times larger than systems without starch. Moreover,
515
membranes prepared from cellulose sulfate related PEC were also applied in
516
membrane separation of gas mixtures (Schwarz et al., 2001; Tamaddondar et al.,
517
2014).
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518
5. Conclusions and future perspectives
520
Cellulose sulfate is a cellulose derivative with unique biological properties. Its
521
bioactive and ionic nature made it a promising candidate for live organism
522
immobilization and even can be used as pharmaceutical active ingredients in disease
523
treatments. This review presented a summary of current research on cellulose sulfate.
524
The synthesis methods were discussed and the emphasis was focused on its
525
application in biotechnological fields. Nevertheless, cellulose sulfate is still a
526
lab-product without commercialization. The materials used in research are most
527
individually prepared. Therefore, results from different groups are not comparable and
528
sometimes lack consistence. It is important to develop affordable and robust synthesis
529
pathways to obtain products with reliable quality, and also explore techniques and
530
methods for clarifying their chemical structures. Furthermore, regioselective synthesis
531
of cellulose sulfate is vital in fulfilling high-demanding requirements from biological
532
industry.
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Acknowledgements
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This work was financially supported by the National Natural Science Foundation of
536
China and the Doctoral Programs Foundation of Ministry of Education of China (No.
537
20110101130007).
538
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1057 1058 1059 1060 1061 1062
cr
us
an
M
ed pt
1056
Ac ce
1055
ip t
1043
1063 1064 1065 1066 55
Page 54 of 56
1067 1068 1069 1070
ip t
1071 1072
cr
1073
Figure captions:
1075
Figure 1. Repeating units of some naturally occurring polysaccharide sulfates and
1076
cellulose sulfate.
an
us
1074
1077
Figure 2. Relationship of viscosity, degree of substitution and soluble part percentage
1079
of cellulose sulfate synthesis by heterogeneous pathways.
M
1078
ed
1080
Figure 3. Structures of chemicals used in the preparation of polyelectrolyte complexes
1082
(PEC) with cellulose sulfate.
pt
1081
Ac ce
1083 1084
Figure 4. Blank capsules prepared with chitosan and cellulose sulfate. Adapted with
1085
permission from reference (Wang et al., 2009a). Copyright (2009) American
1086
Chemical Society.
1087 1088
Figure 5. Schematic diagram of the layer-by-layer assembly with chitosan and
1089
cellulose sulfate. Adapted with permission from reference (Xie et al., 2009).
1090
Copyright (2009) American Chemical Society.
1091 1092
Figure 6. Schematic diagram of biological material encapsulation with polyelectrolyte 56
Page 55 of 56
complexes formed by cellulose sulfate and poly-dimethyl-diallyl-ammonium chloride
1094
(PDMDAAC). Adapted with permission from reference (Gericke et al., 2009a).
1095
Copyright (2009) WILEY-VCH Verlag GmbH & Co..
Ac ce
pt
ed
M
an
us
cr
ip t
1093
57
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