BIBLIOGRAFÍA

Polyanhydrides possess high hydrolytic instability and are used primarily for drug delivery. These are highly reactive materials which degrade by surface erosion and have been investigated for the delivery of a variety of drugs, proteins, and growth factors including chemotherapeutic agents, insulin, heparin, growth factors, and alkaline phosphatase.

Other biodegradable polymers used as a biomaterial include polyorthoesters, polycarbonates, and poly(p-dioxanone).

6.4.6 Polyurethanes

Polyurethanes have been sold commercially since the 1930s for a variety of applications including insulation, seat covers, and others. They were investigated for biomedical applications starting in the 1960s. Polyurethanes can be fabricated from isocyanates, which can be either aliphatic or aromatic. The isocyanates react with organic hydroxyls to form the urethane (―O―CO―NH―) linkages. The chemical structure of polyurethane is shown inFigure 6.12. Polyurethanes can be synthesized to have both hard and soft segments. This versatility can result in a wide variety of mechanical and physical properties. Pre-polymerized diisocya- nates, such as 4,4-metyl-diphenyl-diisocyanate with a diol as a chain extender, are commonly used to create hard segments. The soft segments can be polyether glycols such as polyethylene glycol. The relative ratios of the hard and soft segments and their respective molecular weights can yield stiffer or softer mater- ials and determine their hydrophilic nature.

Because of their good mechanical properties and blood biocompatibility, poly- urethanes have been used for a number of biomedical applications including leads for pacemakers, catheters, heart valves, and ligament reconstruction.

6.4.7 Silicones

The chemical structure of silicone is shown inFigure 6.13. These polymers are characterized by alternating silicon and oxygen atoms in their backbone. Organic groups are attached to the silicon atoms to complete the repeating unit which is known as siloxane. The most common organic group is the methyl group, and the attachment of the methyl group on silicones forms polydimethylsiloxane or PDMS. Other groups such as vinyl or phenyl can be substituted for the methyl group. The combination of organic groups attached to a non-organic backbone gives silicone polymers a range of unique properties. As a result, they are used widely in the construction, aerospace, and electronics industries, in addition to the biomedical industry.

Silicones can be cross-linked to form elastomeric 3D networks. The cross- linking can be achieved using different techniques including radicals, or conden- sation and addition type reactions. In most cases,fillers are used to enhance the mechanical properties and hardness of these silcone elastomers. For most medical applications, fused silica is used as thefiller. Particles (10 nm) of this amorphous material fuse to form aggregates, which in turn interact with other aggregates to form agglomerates with high surface area. The silica is added to the elastomer prior to cross-linking. The polymer forms hydrogen bonds with the silica and attaches to the large surface area of the nanoparticles. This gives the polymer good tensile strength, high elongation ability, and higher viscosity. The silicones used for biomedical applications usually have a glass transition temperature below room temperature.

Compared to polymers with a carbon backbone, siloxane molecular chains are highlyflexible and can have a variety of configurations due to low resistance to rotation, low inter-chain interactions, and larger bond lengths and angles. The

C

(

)

(

)

Chemical structure of polyurethane (PU).

n O R R R R R R Si O Si O Si Figure 6.13

chains orient themselves to present the maximum number of methyl or other groups to the outside, which makes them hydrophobic. These materials can easily formfilms and have a high permeability for gases such as nitrogen, oxygen, and water vapor.

Silicone elastomers are used extensively in the biomedical industry. They have good blood biocompatibility and thus are used for many cardiovascular applica- tions including catheters. In the area of orthopedics, they are used for prostheses to replace finger joints, carpal bones, and toes. They also have large-scale use in breast reconstruction and augmentation as these procedures often use silicone- based implants. Silicone-based implants are also used as for jaw augmentation, chin augmentation, and nasal supports. In general, implants of this material are successful, although there have been reports that the gradual deterioration of the elastomer can lead to the failure of prostheses such asfinger joints.

6.5 Hydrogels

Gels are solid, jelly-like materials, which exhibit noflow when in a steady state. In general, hydrogels are 3D structures in which hydrophilic, water-insoluble, poly- meric chains are dispersed in water and maintain their shape due to the presence of cross-linking and strong water retention. The cross-linking in hydrogels can be physical (chain entanglements) or chemical (van der Waals, covalent, ionic, or hydrogen bonds). Hydrogels can be colloidal in nature with water as the disper- sion medium. Because of their physicochemical properties and high water content (they can contain more than 99.9% water), hydrogels have found numerous applications in the pharmaceutical and biomedicalfields.

Hydrogels have polymeric structures that are dispersed in water where their molecules are tightly bound to water molecules, leading to the formation of a swollen semi-solid structure. Shown in Figure 6.14 is a representation of the interaction of a polymeric chain with water molecules. The water-holding capacity of the hydrogel is an intrinsic property of the polymer and depends on the chemical nature of the polymer’s backbone and more importantly on the chemistry of its functional groups. However, the shape and strength of the hydrogel depend

Figure 6.14

Schematic representation of interaction (absorption) of water molecules (circles) on a polymeric chain.

on the type and degree of cross-linking. Figure 6.15a illustrates a network of polymeric chains in dry form. When mixed with water, the polymeric chain interacts with water molecules and subsequently causes swelling (Figure 6.15b).

Hydrogels can be classified in a variety of ways. For example, they can be classified based on the source of the polymer (natural or synthetic), or they can be categorized based on their constituents or method of preparation. Homopolymer hydrogels consist of polymeric chains containing a single type of hydrophilic monomeric unit which is cross-linked. Copolymer hydrogels use cross-linked polymers that have two types of monomer, at least one of which is hydrophilic. Multipolymer hydrogels have polymers with more than two types of monomer. Interpenetrating network hydrogels are prepared byfirst producing a cross-linked network. This network is then infiltrated with another monomer solution, which is then reacted to form its own network enmeshing thefirst network. Other classifi- cation systems are based on the hydrogels’ ionic charge, structure, type of cross- links, or application (Table 6.1).3

Hydrogels based on natural polymers like chitosan, gelatin, and alginate can have variations in their composition and thereby in their properties. Synthetic polymers such as acrylate-based polymers, on the other hand, can be produced with highfidelity in their molecular weight and composition; hence their physi- cochemical properties are more consistent and uniform than natural polymer- based hydrogels.

Depending upon the type or overall charge of the hydrogel needed, a variety of functional groups can be utilized for synthesis of the polymer.Table 6.2 shows examples of different functional groups and the type of hydrogel charge obtained. In recent years, there has been a surge in the synthesis of smart polymers, which can be used to formulate stimuli-responsive hydrogels. Smart polymers can exhibit a rapid change in water affinity when an environmental factor (pH,

(b) (a)

Figure 6.15

Schematic representation of (a) network of polymeric chains in dry form, and (b) water molecules absorbed onto polymeric chains in a hydrogel leading to water-swollen 3D structure.

temperature, light) is changed. Stimuli responsive hydrogels are usually revers- ible in their nature and show transition from solution (sol) to gel form depending on the stimulus presented. Poly(N-isopropyl acrylamide) (PNIPAm) is a polymer highly studied for its temperature-regulated sol–gel transition. This polymer has both hydrophilic and hydrophobic moieties in its structure. When dispersed in water at a temperature lower than 32 C, hydrophilic interactions with water molecules dominate and the polymer chains stay in extended form, giving it a solution form. When the temperature is raised above 32 C, the hydrogen bonds between the polymer and the water molecules become less stable, and hydrophobic interactions between isopropyl groups on the polymer become thermodynamically favored leading to the formation of compact poly- mer structures and subsequent precipitation of the polymer in the solvent. The temperature at which this transition begins is known as the critical temperature for that solvent–polymer pair. The schematic inFigure 6.16depicts the sol–gel transition for temperature-responsive polymers.

Table 6.1 Classification systems for hydrogels

Classification Property/type

Source Natural

Synthetic Component or method of preparation Homopolymer

Copolymer Multipolymer

Interpenetrating polymer

Electric charge Anionic

Cationic Neutral Zwitterion

Physical structure Amorphous

Semi-crystalline Hydrogen bonded

Cross-link Physical entanglement

Covalent bond

van der Waals interaction Hydrogen bond

Function Stimuli responsive

Superabsorbent Biodegradable

The stimulus for sol–gel transition can also be provided by pH. Hydrogels that are pH sensitive are formed by polyelectrolyte polymers which have weak acids or bases in their structure and can accept or release protons depending on the pH of the environment. The transition of such polymers from compact to expanded state Table 6.2 Functional groups for polymers used for hydrogels

Functional group Charge Example

Carboxyl, sulfonic C R S O R O O O O Anionic Acrylates Quaternary ammonium ⊕ R2 R N R₄ R3 Cationic Chitosan Non-ionic groups C H2 C n NH CH CH3 H3C O H C Neutral Poly-NIPAm

Carboxylic and quaternary ammonium Zwitterion Polypeptides

> Critical temperature

< Critical temperature

Figure 6.16

Temperature-dependent sol–gel transition. Below the critical temperature, the polymer is in expanded form due to hydrophilic interactions with water molecules. Above the critical temperature intra- and inter-chain hydrophobic interactions lead to the formation of compact polymer aggregates surrounded by water molecules.

can be orchestrated by changing the pH. Polyacidic polymers are non-swollen at low pH and expand at high pH because ionization at high pH values leads to solubilization. On the other hand, polybasic polymers show the opposite behavior compared to the polyacidic polymers. Ionization of polyelectrolytes with change in the pH is illustrated inFigures 6.17and6.18.

Similarly, other types of stimuli-responsive hydrogels also utilize the effect of stimulus on the water affinity of the polymer chains to achieve sol–gel transitions.