Living cells can produce material at low temperature and low pressure and also produce no toxic byproducts. Biopolymer research area is most active and better funded. Protein polymer research is focused on high-technology applications, such as elastomers, adhesives, bioceramics, and electro-optical materials.
There is increasing commercial interest into bioadhesives due to their biocompatibility. Also health hazards due to volatile organic compounds emissions from the synthetic adhesives and environmental concerns are the reasons for interests in bioadhesives. Rising oil prices are also the driving force for research in bioadhesives as an alternative to synthetic adhesives. Compared to current petroleum derived products, biopolymer based adhesives are expected to offer reduced price, a lesser degree of price volatility, and a more favorable environmental footprint.
They are useful for biomedical applications involving skin and other body tissues. To date, commercial applications have been limited to the use of genetically engineered adhesives for fixing mammalian cells to culture vessels. Because of extremely high production costs, these products will probably have limited success.
Bioadhesives are natural polymers that can act as adhesives. The term is sometimes used more loosely to describe glue formed synthetically from biological monomers such as sugars, or to mean a synthetic material designed to adhere to biological tissue.
A bioadhesive can be defined as any substance that can adhere to a biological substrate and is capable of being retained on that surface for an extended period of time.
Bioadhesive may consist of protein or carbohydrate such as gelatin or starch. There is search for highly effective adhesives in natural world. Bioadhesives secreted by microbes or marine mollusks are being searched with a view for mimicry.
A bioadhesive polymer is a synthetic or natural polymer which binds to biological substrates such as mucosal membranes. Such polymers are sometimes referred to as biological ‘glues’ because they are incorporated into drugs to enable the drugs to bind to their target tissues, line passageways and structures in the body that lead to the outside environment such as the mouth, respiratory tract, gastrointestinal tract, nose and vagina. They secrete a viscous fluid known as mucus, which acts as a protective barrier and also lubricates the mucosal membrane. The primary constituent of mucus is a glycoprotein known as mucin as well as water and inorganic salts.
Bioadhesives includes a broad variety of different concepts: (i) natural adhesives, (ii) biological adhesives, (iii) biocompatible adhesives, and (iv) biomimetic adhesives and (v) bioinspired adhesives.
(i) The term natural adhesive describes substances that are formulated from partially or totally bio-based raw materials, which are employed as adhesives in man-made technology, but are not substances used by biological systems as glues.
(ii) The term biological adhesive refers specifically to adhesive secretions of natural organisms in marine and other wet environments, or those produced on land.
(iii) A different concept refers to what is named as biocompatible adhesive, including any natural or synthetic adhesive that interfaces with living tissues and biological fluids, and is suitable for short-/long-term biomedical applications. Specific mechanisms of adhesion found in nature are discussed – interlocking, suction, friction, dry and wet adhesion, gluing – to get inspiration for the development of new synthetic adhesives.
(iv) Biomimetic adhesives are synthetic adhesives designed to closely mimic the molecular structure and mechanisms of adhesion found in nature.
(v) Bioinspired adhesives are synthetic adhesives whose design is inspired in biological concepts, mechanisms, functions, and design features.
Commercial Progress and Examples of Applications
- Bioadhesive drug delivery formulations were introduced in 1947 when gum tragacanth was mixed with dental adhesive powder. The aim was to deliver Penicillin into the oral mucosa. This later became Orabase®, a formulation used to treat mouth ulcers. This product is available as a paste which will stick to the wet surfaces of the mouth and form a protective film over the mouth ulcer. Orabase paste contains polymers such as gelatin, pectin and carboxymethylcellulose.
- Acacia gum – This natural polymer is a dried gum obtained from the stem and branches of the tree Acacia senegal. It is used as a thickener in pharmaceuticals.
- Alginic acid – Is a natural polymer found in the cell walls of brown algae. It is widely used in the manufacture of alginate salts such as sodium alginate which is a constituent of Gaviscon liquid®.
- Carbomers – Are polyacrylic acid polymers widely used in the pharmaceutical and cosmetic industries as thickening agents. Carbomers have a huge advantage in formulation science because they adhere strongly to mucosal membranes without causing irritation, they exhibit low toxicity profiles and are compatible with many drugs.
- Hydroxypropyl methylcellulose (HPMC) – This polymer is included in preparations used to moisten contact lenses and in oral gels.
- Sodium hyaluronate – A high molecular weight biological polymer made of repeating disaccharide units of glucuronic acid and N-acetyl-D – glucosamine. This polymer is used during intraocular surgery to protect the cornea and also acts as a tear substitute in the treatment of dry eyes.
Other examples of polymers include: pectin, polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), tragacanth.
- Sustainable Adhesives Products Ltd. specializes in the development and manufacture of Biodegradable and Compostable adhesive products made from renewable and replenishable resources.
- Henkel company has its PROLOCTM bioadhesives for transmucosal drug delivery. PROLOC bioadhesive powders adhere immediately to the nasal mucosa and remain in place until fully eroded. PROLOC bioadhesives are compatible with hydrophilic as well as lipophilic active ingredients. PROLOC bioadhesives can be safely used for repeated applications. PROLOC bioadhesives are manufactured using USP ingredients, enabling a direct and easy path to regulatory approval.
- One of the newest bioadhesives on the market enables drugs to be delivered through the inside of the mouth, nasal passages and other mucus membranes instead of just through skin. It adheres extremely well to the soft, wet mucus membranes of the body because these adhesives are made from starch-polyacrylic acid blends, which then completely erode and disappear. Drug makers are able to put their medicine into tablet, film or powder form, and the patient is able to attach the product directly to a mucus membrane, providing a means for controlled delivery of drugs to specific areas of the body or systemically (throughout the body).
- Bioadhesive is used during knee-cartilage repair surgery. Bioadhesives have been misused to enhance the colours of fish by use of bioadhesive paints.
- JSJ Pharmaceuticals presents Aclaro PD, a bioadhesive emulsion formulated with 4% hydroquinone and the PharmaDur bioadhesive delivery system for the management of melasma and hyperpigmentation disorders. Aclaro PD does not contain propylene glycol or steroids and is formulated with sunscreens for UVA and UVB protection. The PharmaDur delivery system creates an invisible, breathable matrix providing continuous release of medication to applied areas.
- ProNectin was the first engineered protein polymers to be introduced commercially. It was designed to serve as an adhesive coating in cell culture vessels. The polymer was customized to have two distinct peptide blocks: one block possesses the strong structural attributes of silk; the other has the cell-binding properties of the human protein fibronectin. The peptide blocks were chosen after analyzing which particular structures could provide the desired physical, chemical, and biological properties. ProNectin F has demonstrated excellent adhesion to plastic surfaces such as polystyrene and thus can be used to attach mammalian cells to synthetic substrates.
- Marine mussel adhesive protein is a formaldehyde-free natural adhesive that demonstrates excellent adhesion to several classes of materials, including glasses, metals, metal oxides, and polymers. Computer aided design (CAD) patterning of various biological adhesives using piezoelectric inkjet technology has been studied. A MEMS-based piezoelectric actuator was used to control the flow of the mussel adhesive protein solution through the ink jet nozzles. Fourier transform infrared spectroscopy (FTIR), microscopy, and adhesion studies were performed to examine the chemical, structural, and functional properties of these patterns, respectively. FTIR revealed the piezoelectric inkjet technology technique to be nondestructive. Atomic force microscopy was used to determine the extent of chelation caused by Fe(III). The adhesive strength in these materials was correlated with the extent of chelation by Fe(III). Piezoelectric inkjet printing of naturally-derived biological adhesives may overcome several problems associated with conventional tissue bonding materials. This technique may significantly improve wound repair in next generation eye repair, fracture fixation, wound closure, and drug delivery devices.
The chemical structure from the mussel’s adhesive protein has been put into the design of an injectable synthetic polymer. The bioadhesive, called iCMBAs, adhere well in wet environments, have controlled degradability, improved biocompatibility and low manufacturing costs. It puts them above fibrin glue and cyanoacrylate adhesives. iCMBAs are useful for internal organ surgery as tissue adhesives and sealants as well as for external applications. iCMBAs provide 2.5 to 8 times stronger adhesion in wet tissue conditions as compared to fibrin glue. They stop bleeding instantly, facilitate wound healing and close wounds without use of sutures and offers controllable degradation. iCMBAs are non-toxic and cause no allergy.
Sea mussel adhesive Recombinant DNA technology has also led to the development of a bioadhesive based on a protein from the sea mussel Mytilus edulus. Researchers have genetically modified yeast cells to produce the basic mussel protein. An enzyme-catalyzed process (the enzyme-a tyrosinase-modifies the tyrosine amino acids in the protein) was also developed to convert this recombinant protein into a true adhesive. This polymer could be used as a marine coating, as a wetting agent for fibers in composite materials, or as a dental or surgical adhesive. It might be employed also as a sealant during eye surgery. Experimental quantities of the genetically derived sea mussel adhesive were at one time selling for about $45 per milligram, or $20 million per pound). However, over the long term, genetic techniques may allow production to be scaled up significantly at reasonable cost.
- The goal is creation of a transparent, soft and flexible ocular adhesive that can replace the need for sutures. However, the right product—one that is safe, effective, physician-friendly, patient-gentle and acceptably priced—has remained elusive. Cataract surgeries, corneal transplants, lacerations from trauma, leaking blebs—all could benefit from an adhesive application. This could avoid some of the possible complications associated with suturing, such as infection, astigmatism and corneal neovascularization. Cyanoacrylate-based adhesives and fibrin glue are the most commonly used suture substitutes in ophthalmology, and both are used off-label in the United States. Fibrin glue, was first created as a biologically derived adhesive almost a hundred years ago. It imitates the end of the coagulation cascade by adding thrombin to a solution of human fibrinogen. It is mass-produced from pools of human plasma. Fibrin glues are fast-acting and biodegradable but have relatively poor adhesion strength. They may also have risk of transmission of blood-borne diseases and potential for allergic reactions. Cyanoacrylate, also termed ‘crazy glue’ or ‘super glue,’ has been used for about 20 years for healing corneal perforations. Cyanoacrylates, once used mainly in the management of corneal perforations and severe thinning, are compounds with very high tensile strength that rapidly polymerize on contact to form a strong bond. The edges can be rough and sharp on the surface. Cyanoacrylate adhesives are super glues and offer strong adhesion, rapid setting time and strong adhesion to tissue, but they degrade slowly and may cause toxicity, often limiting their use to external applications. Cyanoacrylates is hard, and edges can be sharp on the surface. It can tend to be uncomfortable and may require the patient to wear a bandage contact lens. New biomaterials not only promise to provide a nice coating for healing, but also may constitute a way to deliver antibiotics to the cornea without the need for eyedrops. After FDA approval next challenge will be their pricing.
- The plywood industries are currently using synthetic resin adhesives based on petroleum resources. Cost the petroleum product is increasing day to day which influences the cost of the adhesive. A number of natural materials are available which have in their molecular architecture units resembling phenol /formaldehyde and are capable of undergoing reaction similar to phenol/formaldehyde. Due to their natural origin, these are available on a renewable basis thereby avoiding continued dependence on petroleum resources. These materials can be synthesized to form resin adhesives and also minimizes the pollutant levels. Different bio materials are being tried to make resin formulations to replace existing resin systems in panel industry.
Advantages of Bioadhesives in Plywood Industry –
- Development of the bio- adhesive system helps in the Utilization of bio materials obtainable from natural renewable source.
- There will be reduction in the use of petroleum based chemicals.
- There will be reduction in the cost of the resin.
- It will minimize the emission of formaldehyde.
- Disposal of industrial wastes for better utilization, thereby reducing the pollution problems
- Shellac is an early example of bioadhesive used with commercial interests.
- Commodity wood adhesives based on bacterial exopolysaccharides have been developed.
- USB PRF/Soy 2000, a commodity wood adhesive that is 50% soy hydrolysate and excels at finger-jointing green lumber.
- Mussel adhesive proteins can assist in attaching cells to plastic surfaces in laboratory cell and tissue culture experiments.
- The Notaden frog glue is under development for biomedical uses, e.g. as a surgical glue for orthopedic applications or as a hemostat.
- Mucosal drug delivery applications. For example, films of mussel adhesive protein give comparable mucoadhesion to polycarbophil a synthetic hydrogel used to achieve effective drug delivery at low drug doses. An increased residence time through adhesion to the mucosal surface, such as in the eye or the nose can lead to an improved absorption of the drug.
Production Methods for Bioadhesives
- Direct chemical synthesis, e.g. incorporation of L-DOPA groups in synthetic polymers.
- Fermentation of genetically engineered bacteria or yeasts that express bioadhesive protein genes.
- Farming of natural organisms (small and large) that secrete bioadhesive materials.
Biological adhesives are having impressive performance in nature. Understanding their mode of action may be of help for development of synthetic counterparts with improved functions. These bio-inspired adhesives will provide elegant solutions to our requirements. Multidisciplinary approach may give innovative outputs in the field of adhesives.
Poly(amino acids) Bioadhesives
Bioadhesives based on poly(amino acid) with potential to bond to soft tissues have been reported. They are homopolymer poly(amino acids), mixtures of poly(amino acids) and amino acids, and blends of different poly(amino acids). Adhesive performance has been tested in tension on glass surfaces, chondroitin sulfate surfaces, as well as bovine cartilage surfaces. The amino acid structural units contained acidic, basic, or polar side chains and were found to adhere reasonably well to the surfaces of glass and chondroitin sulfate. The formation of polymer-monomer complexes with the addition of a basic monomer such as L-lysine to negatively charged polymers such as poly(L-aspartic acid) and poly(L-glutamic acid) was found to result in greater adhesive strength relative to homopolymers. Further improvement in adhesion was observed in blends of poly(L-lysine) with polar poly(amino acids) such as poly(L-asparagine). Adhesion on wet cartilage surfaces was the weakest measured but a priming approach designed to form electrostatic or hydrogen bonds appears promising.
(I) Bioadhesives in Drug Delivery
Drug delivery systems using bioadhesives usually adhere to membrane surfaces or the mucin layer coating such surfaces. The majority of the targeted areas used in drug delivery have a coating of mucus, and bioadhesive polymers that attach to this mucus coating are generally called mucoadhesives.
Their residence times on these surfaces are controlled by whether the bioadhesive is water soluble or insoluble. In the case of water-soluble bioadhesives, contact time is generally only a few hours, depending on the adhesive and flow of biological fluid at the site of drug administration. Water-insoluble polymers, in contrast, remain in place until the mucin or tissue replaces itself, typically a period of about 4 to 72 h.
Contact between the adhesive and the mucosal membrane or its coating is a two-step process, (i) the initial contact between the bioadhesive and substrate and (ii) the subsequent formation of bonds between the two surfaces. Success of the initial contact appears dependent on similarity of physicochemical properties between the adhesive and substrate and is often associated with ‘‘wetting’’ of the substrate surface. Formation electrostatic, hydrophobic, or hydrogen bonds, permits the bioadhesive (and drug delivery system) to attach to the substrate.
More recently, researchers have studied bioadhesion by measuring viscometric differences in a mixture of polymer and gastric mucin.
Factors important in Muco-bioadhesion in Drug Delivery
(i) Physicochemical characteristics of the bioadhesive, the substrate mucin-epithelium surface), and the drug.
(ii) Physiological parameters of the targeted tissue
Most delivery systems utilizing bioadhesives are designed to be topically applied to a targeted tissue. Drug delivery systems using bioadhesives can be applied to many areas of the body, such as the (i) oral cavity, (ii) gastric, (iii) intestinal, (iv) rectal, (v) vaginal, (vi) ocular, and (vii) dermal areas. Each tissue type has its own unique properties which can be exploited for the delivery of drugs. Each biological membrane has its own permeability, enzymatic activity, and immunology, which have to be taken into consideration if both satisfactory bioadhesion and improved bioavailability of drug are to be achieved.
(II) Bioadhesives for Surgery
The bioadhesives are specially formulated in accordance with the requirements for each surgical process. ADAL-1 and ADAL-2 are adhesive formulations optimized for strabismus surgery and conjunctiva surgery, respectively. These formulations are protected by respective patents.
These ADAL adhesives have advantages over other adhesives intended to be used for internal and external body use. Their main advantages are:
- Low economic cost.
- Controllable sterilization from synthesis or preparation.
- Easy to handle because they are chemically stable formulations.
- Fast polymerization of the product, but not instantaneous. The surgeon has few minutes for readjusting.
- The adhesion of these new formulations maintains the tissue substrates firmly adhered during the wound healing process.
Bioadhesives from Microalgae
Navicula spp (Diatom) secrete EPS bioadhesive through raphe. P. viridis attaches to glass surface through adhesive mucilage secretions. Spirulina platensis also produces a bioadhesive substance. It will be economically viable to extract bioadhesive from microalgae if Algae full utilization concept is implemented. Thus microalgae for human nutrition, microalgae for animal feed, microalgae for specialty chemicals, microalgae for antioxidants, should be thought of along with extraction of bioadhesive from microalgae.
For recovery of bioadhesive from microalgae, first lipidic fraction is extracted. Then separation of polypeptide plus polysaccharide fraction is done. Then bioadhesive product is obtained.
Brian K. Irons, Joseph R. Robinson, Bioadhesive, Chapter 48, Handbook of Adhesive Technology, Second Edition (Revised), Taylor & Francis Group, LLC (2003)
- Technology Offer – Synthesis and Characterization of Bioadhesives for Surgery, University of Alicante, Spain
- Bioadhesive, in Wikipedia, the free encyclopedia.
- Lori Baker Schena, “Bioadhesives Make Some Advances”, EyeNet Magazine, Jan. 2011, American Academy of Ophthalmology.
- Indian Plywood Industries Research & Training Institute http://www.ipriti.gov.in/
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- Researchers Develop New Bioadhesive, Jan 10, 2013, http://www.psu.edu/
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- Juan C. Suarez, Bioadhesives, Handbook of Adhesion Technology, 2011, pp 1385-1408.
- Bioadhesives from Microalgae, Nieves Gonzalez Ramon, Second Scientific Meeting, Cost Action Bioadhesives, 2011, http://www.feyecon.com