Silicone Biomaterials: History and Chemistry &
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Silicone Biomaterials: History and Chemistry & Medical Applications of Silicones André Colas Jim Curtis Dow Corning Corporation Reprinted from nd Biomaterials Science, 2 Edition with kind permission of the publisher, Elsevier, Inc. To purchase the book Biomaterials Science: An Introduction to Materials in Medicine with a 10% discount, visit www.books.elsevier.com/bioengineering and use the discount code 83661. About the Authors Dr. André Colas Healthcare Industry Scientist André joined Dow Corning in 1978 after completing his PhD in organic physico-chemistry at Brussels’ University (ULB) and worked in different locations on the development of new silicone products. In 1994, he joined the Healthcare business as RD and Production Director of "Laboratoires Dow Corning" in France, working on technologies for the controlled delivery of actives, wound dressings, silicone excipients and surface biocompatibility. In his current role, André is responsible for identifying and validating new and innovative opportunities for Healthcare. Dr. Colas is the author of 15 US patents, 7 articles, and 20 scientific presentations. He is currently a board member of the APGI association, which deals with the formulation of pharmaceuticals in industry. Jim Curtis, Technology Leader, Medical Device Operations Jim’s current activities include project leadership activities with Dow Corning healthcare materials, and the investigation of medical device-associated issues. He has worked in the medical device field for nearly twenty-five years. He helped develop a number of Dow Corning plastic surgery products, most notably the SILASTIC® MSI line of breast implants and tissue expanders. Mr. Curtis has one US and two European patents for developments in breast implant technology. Before joining Dow Corning in 1986, Jim served as Associate Director of Technology and Director of Quality Assurance at Tyndale Plains-Hunter, Ltd., a firm that specialized in hydrophilic polyurethanes for medical applications. He is a member of the Society for Biomaterials; and a graduate of The Cooper Union in New York City, where he earned undergraduate and master degrees in Engineering. 80 2 CLASSES OF MATERIALS USED IN MEDICINE 2.3 SILICONE BIOMATERIALS: HISTORY Historical Milestones in Silicone Chemistry AND CHEMISTRY Key milestones in the development of silicone chemistry— André Colas and Jim Curtis thoroughly described elsewhere by Lane and Burns (1996), Rochow (1987), and Noll (1968)—are summarized in Table 1. CHEMICAL STRUCTURE AND NOMENCLATURE Nomenclature Silicones are a general category of synthetic polymers whose backbone is made of repeating silicon to oxygen bonds. In The most common silicones are the polydimethylsiloxanes addition to their links to oxygen to form the polymeric chain, trimethylsilyloxy terminated, with the following structure: the silicon atoms are also bonded to organic groups, typically CH3 CH3 CH3 | | | methyl groups. This is the basis for the name “silicones,” which CH3 − Si − O − Si − O − Si − CH3, was assigned by Kipping based on their similarity with ketones, | | | because in most cases, there is on average one silicone atom CH3 CH3 CH3 for one oxygen and two methyl groups (Kipping, 1904). Later, n as these materials and their applications flourished, more spe- (n = 0,1, ...) cific nomenclature was developed. The basic repeating unit These are linear polymers and liquids, even for large values became known as “siloxane” and the most common silicone is of n. The main chain unit, –(Si(CH ) O)–, is often represented polydimethylsiloxane, abbreviated as PDMS. 3 2 by the letter D because, as the silicon atom is connected with two oxygen atoms, this unit is capable of expanding within the R CH3 | | polymer in two directions. M, T and Q units are defined in − Si −O− andifRisCH , − Si −O− | 3 | a similar manner, as shown in Table 2. R CH The system is sometimes modified by the use of super- 3 n “siloxane” “polydimethylsiloxane” script letters designating nonmethyl substituents, for example, h = φ Ph = D H(CH3)SiO2/2 and M or M (CH3)2(C6H5)SiO1/2 Many other groups, e.g., phenyl, vinyl and trifluoropropyl, (Smith, 1991). Further examples are shown in Table 3. can be substituted for the methyl groups along the chain. The simultaneous presence of “organic” groups attached to an “inorganic” backbone gives silicones a combination of unique Preparation properties, making possible their use as fluids, emulsions, compounds, resins, and elastomers in numerous applications Silicone Polymers and diverse fields. For example, silicones are common in the The modern synthesis of silicone polymers is multifaceted. aerospace industry, due principally to their low and high tem- It usually involves the four basic steps described in Table 4. perature performance. In the electronics field, silicones are used Only step 4 in this table will be elaborated upon here. as electrical insulation, potting compounds and other applica- Polymerization and Polycondensation. The linear [4] and tions specific to semiconductor manufacture. Their long-term cyclic [5] oligomers resulting from dimethyldichlorosilane durability has made silicone sealants, adhesives and waterproof hydrolysis have chain lengths too short for most applications. coatings commonplace in the construction industry. Their The cyclics must be polymerized, and the linears condensed, to excellent biocompatibility makes many silicones well suited for give macromolecules of sufficient length (Noll, 1968). use in numerous personal care, pharmaceutical, and medical Catalyzed by acids or bases, cyclosiloxanes (R2SiO)m device applications. are ring-opened and polymerized to form long linear chains. TABLE 1 Key Milestones in the Development of Silicone Chemistry 1824 Berzelius discovers silicon by the reduction of potassium fluorosilicate with potassium: 4K + K2SiF6 → Si + 6KF. Reacting silicon with chlorine gives a volatile compound later identified as tetrachlorosilane, SiCl4:Si+ 2Cl2 → SiCl4. 1863 Friedel and Craft synthesize the first silicon organic compound, tetraethylsilane: 2Zn(C2H5)2 + SiCl4 → Si(C2H5)4 + 2ZnCl2. 1871 Ladenburg observes that diethyldiethoxysilane, (C2H5)2Si(OC2H5)2, in the presence of a diluted acid gives an oil that decomposes only at a “very high temperature.” 1901–1930s Kipping lays the foundation of organosilicon chemistry with the preparation of various silanes by means of Grignard reactions and the hydrolysis of chlorosilanes to yield “large molecules.” The polymeric nature of the silicones is confirmed by the work of Stock. 1940s In the 1940s, silicones become commercial materials after Hyde of Dow Corning demonstrates the thermal stability and high electrical resistance of silicone resins, and Rochow of General Electric finds a direct method to prepare silicones from silicon and methylchloride. 2.3 SILICONE BIOMATERIALS: HISTORY AND CHEMISTRY 81 TABLE 2 Shorthand Notation for Siloxane Polymer Units At equilibrium, the reaction results in a mixture of cyclic oligomers plus a distribution of linear polymers. The pro- | | portion of cyclics will depend on the substituents along the CH3 CH3 Si–O chain, the temperature, and the presence of a solvent. | | O O | | − − − − − − − Polymer chain length will depend on the presence and concen- CH3 Si O O Si O − − − − − − − − | | O Si O O Si O tration of substances capable of giving chain ends. For example, | | CH CH in the KOH-catalyzed polymerization of the cyclic tetramer 3 3 CH O − 3 octamethylcyclotetrasiloxane (Me2SiO)4 (or D4 in shorthand MDTQnotation), the average length of the polymer chains will depend on the KOH concentration: (CH3)3 SiO1/2 (CH3)2 SiO2/2 CH3SiO3/2 SiO4/2 x(Me2SiO)4 + KOH → (Me2SiO)y + KO(Me2SiO)zH A stable hydroxy-terminated polymer, HO(Me2SiO)zH, can be isolated after neutralization and removal of the remain- ing cyclics by stripping the mixture under vacuum at elevated TABLE 3 Examples of Silicone Shorthand Notation temperature. A distribution of chains with different lengths is obtained. The reaction can also be made in the presence of CH3 CH3 CH3 Me SiOSiMe , which will act as a chain end blocker: | | | 3 3 − − − − − − − .. .. CH3 Si O Si O Si CH3 MDnM ... .... ...Me SiOK + Me SiOSiMe | | | 2 2 3 .. .. → ... .... ...Me SiOSiMe + Me SiOK CH3 CH3 n CH3 2 3 3 .. .. where ... .... ... represents the main chain. CH 3 The Me SiOK formed will attack another chain to reduce the CH3 3 average molecular weight of the linear polymer formed. O CH3 Si The copolymerization of (Me2SiO)4 in the presence of CH3 Si Me3SiOSiMe3 with Me4NOH as catalyst displays a surpris- ing viscosity change over time (Noll, 1968). First a peak or O D4 viscosity maximum is observed at the beginning of the reac- O tion. The presence of two oxygen atoms on each silicon in the cyclics makes them more susceptible to a nucleophilic attack Si CH Si 3 by the base catalyst than the silicon of the endblocker, which is O substituted by only one oxygen atom. The cyclics are polymer- ized first into very long, viscous chains that are subsequently CH3 CH3 CH3 reduced in length by the addition of terminal groups provided by the endblocker, which is slower to react. This reaction can be described as follows: CH3 | cat Me3SiOSiMe3 + x(Me2SiO)4−−−→Me3SiO(Me2SiO)nSiMe3 CH3− Si −CH3 | or, in shorthand notation: CH3 OCH3 TM3 + −−−cat→ ||| MM x D4 MDnM − − − − − − CH3 Si O Si O Si CH3 where n = 4x (theoretically). ||| The ratio between D and M units will define the average CH3 CH3 CH3 molecular weight of the polymer formed. Catalyst removal (or neutralization) is always an important H step in silicone preparation. Most catalysts used to prepare | silicones can also catalyze the depolymerization (attack along CH3− Si −CH3 | the chain), particularly at elevated temperatures in the presence CH OCH of traces of water. 3 3 .. .. .. .. || | ... .... ...(Me SiO) ... .... ... + H O H C H 2 n 2 CH3− Si −O− Si −O− Si −CH3 QM2M M 2 5 || | cat . .... .... .... .... or −−−→ . .. (Me2SiO)y H + HO(Me2SiO)z . .. H Et CH3 OCH3 QM2M M | It is therefore essential to remove all remaining traces of CH3− Si −CH2−CH3 the catalyst, providing the silicone optimal thermal stability.