Recognition templates for biomaterials with engineered bioreactivity

Current Opinion in Solid State and Materials Science 4 (1999) 395–402

Recognition templates for biomaterials with engineered bioreactivity Buddy D. Ratner*, Huaiqiu Shi University of Washington Engineered Biomaterials, Seattle, WA 98195, USA

1. Introduction: why recognition biomaterials? Recognition and specificity are ubiquitous and characteristic motifs used throughout biology. The metaphor of recognition and biological specificity as a ‘lock and key’ fit was first expressed by Emil Fischer a century ago. Since that time, biological recognition and specificity have been noted in enzymes, antibodies, lectins, integrins, DNA, RNA, and saccharides, just to name a few of the systems central to modern molecular biology. Important developments in the evolution of cell and molecular biology in the last two decades include the realization that cells transact their business with their outside world through specific membrane receptors, and that cells communicate with each other via cytokines that are specifically recognized by cell-surface receptors. Also, recognition and specificity are seen in non-biological systems such as petrochemical catalysts, crown ethers and chromatographic separation columns. A Nobel Prize to Donald Cram in 1987 recognized his contributions in defining the chemical nature of molecular recognition. Basically, recognition was described as the correct chemistry arrayed in the correct geometry. Chemical systems exhibiting this defined molecular complexity could be inorganic, organic or organic-biological. Many review articles and books are available on the concepts of molecular recognition [1–5]. The realization of the importance of recognition and specificity to biomaterials also has its roots in the second half of the 20th century. Possibly the first application of biological specificity to biomaterials involved the immobilization of heparin at surfaces to enhance the blood compatibility of materials [6]. Heparin serves as a recognition template to catalyze the complexation of the proteins thrombin and antithrombin III into an inactive form. Initial studies with heparin involved non-covalent modes of surface localization on biomaterials. In 1972, Hoffman et al.

*Corresponding author. Tel.: 11-206-616-9781; fax: 11-206-6169763. E-mail address: [email protected] (B.D. Ratner) 1359-0286 / 99 / $ – see front matter PII: S1359-0286( 99 )00047-9

1999 Published by Elsevier Science Ltd.

published a paper that described the covalent immobilization of heparin, as well as other biomolecules such as streptokinase, to surfaces to impart specific modes of action [7]. This paper was seminal to the field of biomaterials in that the concepts of (1) designing material surfaces based upon well-understood biology and (2) engineering surfaces to initiate specific bioreactions were expressed. Since that paper, a large number of publications describing biomaterials systems with immobilized proteins and peptides have appeared (for example, see [8–16]. The goal of these works is to surface engineer biomaterials to produce a specific, desired bioreaction. Although biospecific biomaterials offer attractive possibilities, the majority of biomaterials are, in fact, nonspecific in their action. Consider a series of materials that are widely used in medicine today: gold, titanium, carbon, alumina, polyurethane, poly(hydroxyethyl methacrylate), polyethylene, silicone rubber, Teflon. This series represents a wide span of materials science properties including metallic, ceramic, glass, polymeric, hydrophilic, hydrophobic, hard soft, etc. If their interactions with biological systems are studied in vitro, wide differences in bioreactivity will be observed in this set. For example, if cell attachment is studied, some materials will be resistant to cell adhesion while others readily attach cells. Among the materials that adhere cells, large differences in adherent cell morphology and growth will be noted. Similarly, if protein adsorption is studied, each of the materials will be observed to adsorb different ratios of proteins from complex protein media, and there will be large differences in the abilities of these surfaces to conformationally alter the adsorbed proteins. This range of behaviors will be noted with blood reaction, bacterial interaction or most any other in vitro biological assay. However, if the materials are implanted in a living organism, all of the materials will exhibit an essentially indistinguishable reaction: after approximately one month, the materials will be found to be encapsulated in an acellular and avascular collagenous bag [17,18]. This collagenous sac (the foreign body capsule) can have a number of downsides in clinical practice. However, more importantly here, it raises an important fundamental question for biomaterials science.

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Why is it that all these materials perform so differently in vitro (i.e. the biological systems interrogate the materials and ‘see’ surface differences), yet, in vivo, the body sees them as all essentially the same? The only commonality between the widely different surfaces in the above set is that they all have non-specifically adsorbed protein layers. These protein films, though different in composition on each material, all contain many different proteins in many different states of denaturation [19,20]. Nature never uses such non-specific protein layers in its normal workings in living organisms. We hypothesize that the layer is seen by the living organism as foreign and the body reacts to it by walling it off. The corollary to this is if we use specific protein layers recognized by the body, we might turn on specific processes and control healing with precision. The proteins and bioreactions that can do this are beyond the scope of this materials-oriented review. However, some hints are contained in a recent publication [21]. How might we exercise precise protein control at the surfaces of biomaterials? The classic approach has in-

volved the immobilization of biomolecules to the biomaterial surface [22]. Though in principle this should be effective, in practice most biomolecules are expensive, unstable and subject to considerable regulatory scrutiny. The template approach puts a stable, non-proteinaceous receptor for the protein of interest on the surface. The surface will then have a high affinity for the protein needed to control the desired biological process, and will concentrate that protein at its surface from the patient’s own body. Templating is a relatively new technology to create such specific protein affinity surfaces. The templating concept is schematically illustrated in Fig. 1. This review article will overview the templating approach for creating biospecific surfaces.

2. Recognition imprints for creating biological templates The template imprinting approach has been applied to a number of biologically relevant substances (Table 1).

Fig. 1. Three techniques for template imprinting of proteins: (a) protein entrapment, (b) microbead surface imprinting, and (c) flat surface imprinting. In (a), protein is first prearranged with functional monomers via non-covalent or covalent interactions, followed by addition of crosslinker. This leads to a crosslinked polymer with entrapped protein. After fragmentation of the polymer and removal of the template, the imprint is obtained with a protein-shaped cavity that has the arrangement of functional groups complementary to the template protein. In (b), protein is first prearranged with functional monomers in the presence of a surface derivatized microbead. After addition of crosslinker, a polymer layer is formed around the surface of the microbead with partially embedded protein. Following extraction of the protein, a binding cavity for the template was created with the surface complementary to the template protein in shape and functionality. In (c), protein is adsorbed to a mica surface, followed by coating with an ultrathin layer of disaccharide. A thin polymeric film is then deposited from an RFGD plasma binding the sugars. The mica is peeled and the protein is removed – a pocket with a shape complementary to the template protein is obtained.

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Table 1 Template-imprinted biomolecules and cells, and their potential biorecognition applications Class

Name

Approach

Application

Reference

Cells

L. monocytogenes and S. aureus B. subtilis E. coli Transferrin, glucose oxidase and ribonuclease Urease, myoglobin, albumin and hemoglobin Hemoglobin, growth hormone, cytochrome, transferrin, myoglobin and ribonuclease Albumin, IgG, fibrinogen, lysozyme, ribonuclease A, glutamine synthetase, a-lactalbumin and streptavidin Galactoside, glucoside, mannoside, fucoside, glucoside and sialic acid Galactose, fructose, xylose and sialic acid Glucose Testosterone, dione, androstadiene, progesterone, corticosterone and cholesterol Testosterone, cholesterol and castasterone Derivatives of Phe, Trp, Tyr, Ala, Glu, Pro and Asp Gly derivative Phe, Tyr, Val, Leu, Ile and Ala Derivatives of Phe–Ala, Trp–Ala, Phe–Trp, Phe–Gly, Ala–Ala, Ala–Gly–Phe and enkephalin (Tyr–Gly–Gly–Phe–Leu) ATP, Adenosine, inosine, derivatives of base A, C, T, U and nucleoside A, C, T, G and U

Bead surface Mineralization Flat surface Microbead surface Entrapment Entrapment

Cell separation, bacteria analysis Microporous biomaterials Cell recognition Bioseparation Bioseparation Bioseparation

[41] [40] [39] [32,33,35] [29] [30,31]

Flat surface

[36–38]

Noncovalent

Biosensor, diagnostics and biomaterials Separation and drug targeting

Covalent Metal coordination Noncovalent

Separation, catalysis and sensor Sensor Separation, diagnostics and sensor

[45–48] [49] [50–55]

Covalent Noncovalent

Separation and sensor Separation

[56–58] [33,59–65]

Covalent Metal coordination Noncovalent

Separation Separation Separation, diagnostics, and drug screening

[66] [67,68] [65,69–72]

Noncovalent

Separation, sensor and catalysis

[73–77]

Proteins

Sugars a

Steroids

Amino acids a

Peptides a

Nucleotide b a b

[43,44]

Include their derivatives. Include nucleosides, nucleotide bases, and their derivatives.

These biotemplates range from small molecules such as sugars, steroids, amino acids, and nucleotides, to macromolecules like peptides and proteins, and even biomolecule assemblies such as cells. The main applications of biotemplate-imprinted materials include: (i) tailor-made adsorbents for bioseparations, (ii) antibody mimics in diagnostic assays, (iii) recognition components in biosensors, (iv) enzyme mimics for biocatalysis, and (v) engineered biomaterials with specific cell and / or protein reactivity. Areas (i)–(iv) have been covered in previous reviews on molecular imprinting [23– 27]. In this article we will discuss recent development in protein and cell imprinting that are of particular interest in the biomaterials field.

2.1. Template imprinting of proteins Numerous applications in separations, biosensors, diagnostic assays, drug targeting, controlled release, and medical implant biomaterials can be envisioned for materials that specifically bind a given protein. Although antibodies and other biomolecules can be used in such applications, their high cost and low stability provide the impetus to develop synthetic materials for specific protein recognition. In addition, appropriate biological agents for protein recognition may not be available for certain applications. Template imprints of proteins as an approach to protein recognition materials is challenging because of the fragile nature, chemical complexity and geometric complexity of

protein macromolecules [28]. Several prerequisites must be satisfied in order successfully imprint proteins to make materials that demonstrate specific recognition. First, an appropriate polymerization reaction should be designed in which the fragile template protein can reasonably well maintain its structural and conformational integrity. Second, following the polymerization, the protein macromolecule must be extracted from the polymer without destroying the structure of the imprinted cavity. Moreover, non-specific protein binding should be minimized for the imprint polymer. Otherwise, specific protein recognition will be overshadowed by non-specific interactions. A number of efforts, more or less fulfilling the above criteria, have been made to imprint various proteins in order to make artificial receptors. These approaches can be categorized as protein entrapment, microbead surface imprinting, and flat surface imprinting (Fig. 1).

2.1.1. Protein entrapment In this approach to protein imprinting, the template protein molecules are entrapped in a bulk polymer, which is then ground up into micron-sized particles allowing for extraction of the surface exposed protein (Fig. 1). Polysiloxane polymers were thus prepared in the presence of urease or bovine serum albumin (BSA) [29]. The entrapped protein was removed by protease digestion and the resulting polymers were evaluated for their ability to rebind the two proteins. Each protein imprint polymer exhibited a slightly preferential binding of its template

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protein. Also, the study using hemoglobin and myoglobin showed that a template protein bound more tightly to its imprint polymer. The authors speculated that complementary protein–polymer interactions were induced by the association of functional silanol monomers with residues on the protein surface during polymerization. Another protein entrapment technique showed highly selective template recognition of proteins [30,31]. Acrylamide was polymerized in the presence of a protein to form a low cross-link density gel for chromatography. The entrapped protein was removed by washing with acetic acid and sodium dodecyl sulfate (SDS). Hemoglobin, cytochrome C, transferrin, human growth hormone, ribonuclease and myoglobin were specifically adsorbed by the columns of their corresponding gels. The specificity was demonstrated by the demonstration that horse myoglobin, but not whale myoglobin, was adsorbed to a column designed for binding the former. This impressive recognition was attributed to the dominance of weak bonds, such as hydrogen bond and dipole–dipole interactions, between protein and the polyacrylamide gel. Therefore, only a template protein can achieve an overall strong binding as a summation of a large number of weak bonds due to the complementarity of two surfaces — the template protein surface and the imprinted cavity surface. On the other hand, non-template proteins cannot adsorb to the ‘inert’ polyacrylamide gel because there are too few binding interactions to overcome brownian and diffusional forces favoring desorption.

2.1.2. Microbead surface imprinting In the protein entrapment approach, some template molecules are permanently entrapped inside the polymer particles, leading to an inefficient use of expensive template protein. The technique of microbead surface imprinting addresses this problem by grafting or coating the protein imprinted polymer on preformed, derivatized silica beads (Fig. 1). In addition, these spherical particles with narrow size distribution are well suited for chromatography. In one early attempt at protein imprinting, the glycoprotein transferrin was allowed to interact with a boronatesilane in the aqueous solution, followed by polymerization onto the surface of silica particles [32]. Since the boronate group interacts reversibly with the sialic acid on transferrin, the idea was that prearrangement of the boronatesilane around the transferrin would lead to the correct positioning of boronate groups, thereby creating a binding cavity specific for transferrin. The polysiloxane-coated silica prepared with transferrin was used in a high-performance liquid chromatography (HPLC) system and shown to have a slight selectivity for transferrin compared to BSA. An alternative approach was based on metal coordination interactions [33]. A metal chelating monomer was

polymerized onto methacrylate-derivatized silica particles in the presence of metal ions and ribonuclease A (RNase A), which contains two surface-exposed histidines capable of coordinating metal ions. The protein was subsequently removed by treatment with EDTA and urea. The resulting silica particles were used as a stationary phase in HPLC. The RNase A-imprinted stationary phase showed, in the presence of metal ions, a higher affinity for RNase A than the BSA-imprinted stationary phase. A related work showed that proper positioning of as few as two metal ions in a complex provides strong binding and a high selectivity for complementary ‘protein analogs’, bis-imidazoles [28]. The bead surface imprinting technique has also been reported for the copolymerization of acrylic acid and acrylamide on silica particles resulting in template imprinted recognition sites for glucose oxidase [34,35].

2.1.3. Flat surface imprinting A new approach to protein imprinting is based on radio frequency glow discharge (RFGD) plasma polymerization / deposition (Fig. 1) [36–39]. Protein was adsorbed to mica, a hydrophilic, molecularly flat surface that is minimally denaturing to proteins. A molecularly thin layer of disaccharide molecules was then coated on the adsorbed protein. Upon drying, this sugar layer complexed with the protein via extensive hydrogen bonding. Then, a smooth thin film of fluoropolymer was deposited from a glow discharge plasma to crosslink the sugar molecules. Following the removal of the mica and the dissolution of the template protein, a polysaccharide coated surface with protein-shaped nanopits was created. This was examined by transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS). Fig. 2 shows an AFM image of such a surface with fibrinogen imprints. Protein adsorption measurements using dadiolabeled protein showed that the imprints of a number of proteins including albumin, IgG, ribonuclease A and lysozyme, exhibited a preferential binding of their corresponding template proteins from protein mixtures [36,37]. Kinetic experiments suggested that protein recognition was due to a dynamic protein adsorption-exchange in which high affinity template protein displaced weakly adsorbed, nontemplate protein on the hydrophilic imprint surface. Higher recognition specificity of the imprints was observed for the template proteins that have higher conformational stability upon adsorption to mica. In another experiment, streptavidin (SA) was micro-patterned via microcontact printing on mica [38]. The resulting RFGD-sugar imprint showed a distinctive pattern of SA adsorbed from a protein mixture when examined by fluorescence microscopy and AFM, indicating specific template recognition. Fig. 3 shows a pattern of anti-SA antibody tagged with 10 nm colloidal gold particles, recognizing the SA molecules specifically

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Fig. 2. A tapping mode AFM image of a fibrinogen imprint. The dark features (dots and grooves) represent surface indentations which are the imprinted replica of the template protein adsorbed to mica in various conformations and orientations. Included is a schematic drawing of fibrinogen.

adsorbed to a patterned SA imprint. Thus, the SA remained active after binding in its recognition pit. The plasma deposition-based imprinting methodology is potentially useful in that large, flat protein imprint surfaces can be used on medical devices and diagnostic chips, while the microparticles or microbeads produced with the other

imprinting techniques are primarily useful in chromatography columns.

2.2. Template imprinting of cells Cell imprinted materials are of potential use in cell

Fig. 3. A tapping mode AFM image of anti-streptavidin tagged with 10 nm colloidal gold. The anti-streptavidin-gold localizes on the surface adsorbed streptavidin (SA) which had recognized the patterned SA imprint area during adsorption from a protein mixture. The bright dots are the colloidal gold particles.

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cultivation, cell sorting, tissue culture, microorganism analysis, and single cell bioreactors. For example, a cell footprint might ‘lock’ its template cell adhered into its natural shape and thus maintain its phenotype. Cells used for template imprinting have focused on bacteria because of their well-defined shape and tolerance to harsh polymerization conditions. A bacteria superstructure, a thread of coaligned multicellular filaments of bacteria, was reported to result in ordered, macroporous silica fibers by template-directed mineralization [40]. E. coli cells were imprinted by RFGD plasma deposition of thin polymeric films, leading to replica indentations of the same size and shape as the template cells [39]. A facile technique called cell-mediated lithography can be used to construct spatially functionalized polymer surfaces [41,42]. A range of chemistries, including an interfacial polycondensation reaction under mild condition and neutral pH, was used to yield multilayer beads with partially embedded bacteria on the bead surfaces. Following the removal of template cells by acid hydrolysis, the polymer beads exhibit anisotropic patches of dimensions complementary to the bacteria in size and shape. It is possible to modify the chemistry of different surface sites to tailor these beads for particular applications.

3. Opportunities, obstacles and outlook for the use of template surfaces in biomaterials The potential for templates as biospecific biomaterials is high. The use of whole proteins on biomaterial surfaces is complicated and expensive and there is the question of stability. Templates would allow recognition biomaterials to be made that used no proteins and exploited the patient’s own proteins. The ‘correct’ protein would concentrate at the surface of the implant, the site where it could be most effective, due to template recognition. What might be needed to make template biomaterials a reality? A few developments will speed this technology to real-world applications:

1. Imprint surfaces fabricated to date have used nonspecifically adsorbed template proteins on the mica surface. Thus, the template proteins are unoriented on the surface and are in various states of denaturation. If every template protein molecule on the flat surface could be oriented, the pits on the surface would also be oriented and the template proteins that bound to the imprint surface would then be oriented. The active domains on the protein could be oriented outward where they would be maximally effective in triggering biospecific processes. 2. We must learn to conformationally stabilize easily denatured proteins on surfaces so they can be usefully imprinted.

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