Polymer Materials for Biomedical Applications

Polymers are the most versatile class of biomaterials, being extensively applied in diverse medical fields such as tissue engineering, implantation, artificial organs, medical devices, prostheses, contact lenses, dental materials and pharmaceutical vehicles.¹  Compared with other types of biomaterials, such as metals and ceramics, polymers can be synthesized in different compositions with a wide variety of structures and properties which permit specific applications.

The recent progress in nanotechnology as well as the active research at the interface of polymer chemistry and biomedicine has opened novel opportunities to use nano-sized polymeric systems in bioengineering, molecular biology, diagnostics, and therapeutics. In this chapter we aim to summarize the types of polymer-based nanostructures applied in biomedical fields and outline the basic criteria for polymer selection.

Polymers used as biomaterials can be naturally occurring, synthetic of combination of both. Natural polymers are abundant, usually biodegradable and offer good biocompatibility.²  A majority of drug delivery systems have been based on proteins (e.g. collagen, gelatine, and albumin) and polysaccharides (e.g. starch, dextran, hyaluronic acid, and chitosan). For example, chitosan and its derivatives have shown excellent biocompatibility, biodegradability, low immunogenicity, and biological activities.^3,4  The principal disadvantage of natural polymers is associated with their structural complexity, which often makes modification and purification difficult. On the other hand, synthetic polymers are available in a wide variety of compositions with readily controlled physicochemical, chemical, mechanical, and biological properties. Advanced polymerization techniques, processing, and blending provide ways for optimizing the polymer mechanical characteristics, diffusive and biological properties. A primary drawback of the majority of synthetic materials is the general lack of biocompatibility, although poly(ethylene oxide) (PEO) and poly(lactic-co-glycolic) acid are notable exceptions.

The role of natural and synthetic polymers of macroscopic dimensions (mm to cm) in biomedical applications such as fabrication of prostheses, implants, and soft contact lenses is well established.¹  During the last two decades an extensive research has been dedicated to understanding the function of nano-structured polymers as biomaterials. Indeed, polymeric nanostructures are predominantly used to design intelligent systems for drug formulations. Polymer therapeutics can be broadly classified into polymer–drug conjugates,⁵  polymer–protein conjugates^6,7  and novel nano-vehicles such as self-assembled block copolymer micelles,^8,9  vesicles,^10,11  DNA/polycation complexes (“polyplexes”),^12,13  block ionomer complexes,^14,15  micro (nanogels)^16–18  and nanocapsules (-spheres)^19,20  (Figure 1.1).

Usually, all subclasses utilize specific water-soluble or biodegradable polymers, either bioactive themselves or an inert parts of drug, gene or protein delivery systems. Polymer–protein conjugates are widely employed for biomedical applications.^21,22  Covalent attachment of a synthetic polymer to biopolymers such as proteins, enzymes, antibodies, usually improves the stability, solubility, and biocompatibility of both components as well as extends the circulation time of the system. Poly(ethyleneoxide) (PEO) (commonly referred to as poly(ethyleneglycol) (PEG)) has become the prototypical “biocompatible” polymer for conjugation with therapeutic peptides, proteins, and antibodies (“PEGylation”).^23–28  Several PEGylated proteins are in clinical use.²⁹  The concept of polymer–drug conjugates is based on the “Ringsdorf's model” implying a drug, a polymeric carrier, and a cleavable covalent link between the two.³⁰  Careful tailoring of the polymer–drug linker is essential for the creation of polymer-based drug delivery system, since the latter has to be inert during transport and allow drug liberation at an appropriate rate. Further elaboration of this model included the incorporation of a targeting motif to ensure delivery of the therapeutic at the desired biological site.^31–33  It is important to mention that the polymer–drug conjugates provide an ideal opportunity for simultaneous delivery of a combination of drugs.³⁴  A number of polymer–drug conjugates are in clinical trials, others are already on the market.³⁵ 

Compared to this first generation polymer therapeutics, the new generation nanosized materials are more advanced (Figure 1.1b). They offer high drug loading capacity, adequate stability in the bloodstream, long circulating properties, and can be designed to enable selective drug targeting with a suitable drug release profile. Polymeric micelles with non-covalently (physical entrapment) or covalently (chemical conjugation) incorporated drugs are extensively studied as promising nanoscopic therapeutics due to their attractive features approaching the requirements for selective dug delivery.³⁶  Some of these systems are presently in phase I or phase II clinical trials.^37,38  Besides the core-shell type of self-assembly structure typical for polymeric micelles,³⁹  depending on the polymer composition and the preparation conditions, amphiphilic block copolymers can also form vesicular structures.¹⁰  These are commonly called “polymersomes”, and reflect the structure of liposomes meaning that a bilayer structure enclosing an aqueous interior is present. Compared with lipid vesicles which possess a number of pharmacokinetic limitations, polymersomes are considered to be more rigid, stable and versatile, and less permeable.⁴⁰  These synthetic shells are being used to encapsulate, protect, target, and release various hydrophilic drugs, proteins, and nucleic acids.^11,41–43  Furthermore, it was demonstrated by Discher et al. that the polymeric vesicles can simultaneously carry hydrophobic drugs (in the bilayer) as well as hydrophilic drugs (in the interior).⁴⁴ 

Modern polymer chemistry is producing an increasing number of complicated polymer architectures, including multivalent polymers,^46,47  branched polymers,⁴⁸  graft polymers,⁴⁹  dendrimers and dendronized polymers,^50,51  block copolymers,⁵²  stars,⁵¹  hybrid glyco-⁵³  and peptide⁵⁴  derivatives, carbon nanotubes,⁵⁵  and nanofibers⁵⁶  (Figure 1.2). In terms of biomedical applications these materials are still at relatively early development stages. However, their unique structural and mechanical properties hold a great promise for drug delivery, bioimaging and tissue engineering research. Their potential advantages include better defined chemical composition, tailored surface multivalency, and creation of defined three-dimensional architecture within either synthetic water-soluble macromolecules or new supramolecular systems such as polymeric nanotubes.⁵⁷  Dendrimers and dendronized polymers are particularly attractive for immobilization of drugs, imaging agents, and targeting moieties since they combine the features of monodisperse nanoscale geometry with high end-group density on their surface.⁵⁸ 

Despite the broad diversity of polymer structures available, the choice of a polymer for biomedical applications remains a challenging task due to the number of criteria it has to satisfy. An additional complication arises from the fact that the polymer–body interactions are currently not well understood.

Materials at the nanometer scale possess unique physicochemical properties including small size, high surface area, chemical composition (e.g. purity, crystallinity, electronic properties), surface structure (e.g. surface reactivity, functionality), solubility, shape, and aggregation. Being of the same size as biological entities the polymeric nanomaterials can readily interact with biomolecules on both the cell surface and within the cell. Due to these properties the nanomaterials can exhibit toxic effect and may represent a considerable hazard for the human body. Polymer biocompatibility or toxicity (term referred to drugs) is a measure of non-specific, unwanted harm that the polymer may elicit towards cells, organs, or indeed the patient as a multi-organ system. It should be noted, however, that the material biocompatibility has to be defined only in the precise context of material use. For example, for blood-contact applications, biocompatibility is determined basically by specific interactions with blood and its components. For applications not involving blood contact, the choice of material depends on its tissue biocompatibility. Indeed, a polymer may be biocompatible in one application but bioincompatible in another. In any case, however, the biocompatibility is an essential characteristic of material for its biomedical utilization.

The general cytotoxicity, hematoxicity, carcinogenicity, teratogenicity, and immunogenicity of many polymer materials has been defined.^59,60  Features such as polymer molecular weight, molecular weight distribution, charge, hydrophobicity and more delicate physicochemical properties, including surface and bulk properties have a profound effect on the polymer biocompatibility, biodistribution, elimination, and metabolism. It is important that a molecular mass of a polymer is correctly chosen to satisfy the requirements for certain application. For instance, the molecular masses of non-biodegradable polymers have to be limited to <40 kDa to ensure eventual renal elimination. It is also known that high molecular weight polymers cannot cross the blood–brain barrier and are not resorbed after oral administration.⁶¹  Individual macromolecules of different chain length present in a polymer sample might significantly affect the polymer biological activity (e.g. toxicity, efficacy). Therefore, the polymer polydispersity index (ratio Mw/Mn; where Mw is the weight average molecular weight; and Mn is the number average molecular weight) is a crucial characteristic of the polymer. Depending on the mechanism of polymerization, some synthetic polymers have very narrow polydispersity. For example, PEG has an Mw/Mn ∼1.01. New synthetic methods (e.g. living free-radical polymerizations) and dendrimer chemistry are moving towards the production of synthetic macromolecules that, like proteins, are monodisperse.

It is important to point out that polycations, as a rule, are significantly more toxic than water soluble natural polymers and polyanions. Nevertheless, a few polycation-based therapeutics have been developed and tested in clinical applications.^33,45,62  For instance, chitosan has been incorporated in a number of oral and injectable drug therapeutics and vaccines.^63,64  An example of a successful synthetic polycation-based polymer therapeutic is “polyoxidonium”, a partially N-alkylated, partially N-oxidized biodegradable copolymer of poly(1,4-ethylenepiperaside).⁶⁵  Polyanions are less cytotoxic, but can cause anticoagulant activity and can also stimulate cytokine release. The few well-known examples of systemically administered anionic polymers include heparin and its synthetic analogs, e.g. highly sulfated glycosaminoglycans.⁶⁶  One example of a synthetic polyanion administered in the body is poly (dicarboxylatophenoxyphosphazene) (PCPP), evaluated in clinical trials as immunoadjuvant in a number of preventive vaccines, such as influenza^67,68  and also as drug carrier.⁶⁹ 

The biocompatibility of a polymer depends also on the specific adsorption of proteins to the polymer surface and the subsequent cellular interactions. These interactions with the surrounding medium are governed mostly by the distribution of functional groups on the biomaterial's surface. For instance, if blood contact is desired, the surface must be nonthrombogenic. The surface load and energy should then be considered, because they regulate the fluid–material interactions within the host. In general, a high charge density or/and hydrophilicity are required to reduce protein adsorption and thus to promote thromboresistance of the surface. Hydrophilic surfaces are essential in applications such as controlled drug delivery and sutures, where a regulated hydrolytic-degradation rate and optimum diffusion characteristics are desirable. Various chemical and physical approaches have been used to optimize specific polymer surface properties and thus improve the polymer biocompatibility.^70–72  Material bulk properties such as permeability, diffusional characteristics and degradation rate must also be considered when selecting polymers for a certain application. Certainly, the polymer bulk properties are determined by its microstructural design. Concerning the permeability, for example, it is known that elastomers are usually permeable to gases and hydrophobic molecules, e.g. polyolefin-based microporous membranes are highly permeable to oxygen. Hydrogels are permeable to water and water-soluble molecules, which is important for drug delivery and dialysis.

For many pharmaceutical applications biodegradable polymers are required. The degradation of the material is needed to ensure its removal from the body through renal clearance. It is essential that non-toxic low molecular weight products are generated as a result of the polymer degradation. Biodegradable polymers (also called bioerodible or bioresorable) may be of natural or synthetic origin (Figure 1.3).

Due to the physicochemical limitations of natural polymers, the synthetic polymers are preferred materials for specific applications. Their biodegradability can be tuned by varying the chemical structure of the polymer. Incorporation of hydrolytically labile groups (e.g. ester, orthoester, anhydride, carbonate, amide, urea, and urethane) (Figure 1.4) into the polymer backbones, and/or grafting side chains with different hydrophilicity or crystallinity can influence the kinetics of biodegradation, as well as the physical and mechanical properties. For example, degradation of synthetic polymer can be limited to 1 week or 1 month, depending on the desired application.

Biodegradation can be of enzymatic, chemical, or microbial origin, and these may operate either separately or simultaneously and are often influenced by many other factors (Table 1.1).⁷³ 

Poly(ester)s, poly(orthoester)s, poly(anhydride)s, poly(phosphazene)s, poly(phosphoester)s, poly(amide)s and few natural polymers (i.e. proteins, polysaccharides), as well as networks, copolymers, blends, and micro/nano-objects based on these polymers, have been commonly studied and used as biodegradable biomaterials.^74,75  Poly(ester)s, namely, poly(caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymers, poly(lactic acid-co-glycolic acid) (PLGA), are one of the best defined biomaterials with regard to design and performance.^74,76,77 

The ability to design polymers with controlled degradation profile, mechanical and processing properties has opened opportunities for the development of modern polymer-based drug delivery devices such as biodegradable micro/nanoparticles. The latter are particularly attractive with their potential to provide a more effective alternative for release of bioactive molecules then liposomes. Polymer particles are more stable and offer longer-term release of cancer therapeutics in vivo.⁷⁸ 

Furthermore, novel “smart” biomaterials with improved biological action (e.g. for triggered drug release) are now emerging as a new generation of therapeutics. These “intelligent” systems are based on polymers that undergo structural changes in response to various physical, chemical, and biological stimuli such as pH, temperature, and electrical and optical fields. The use of smart polymers allows a controlled drug release at a predetermined time/or place.

Although the polymer biocompatibility and biodegradability are criteria of primary concern for biomedical applications, the manufacturing process also needs to be considered. The polymeric devices must be prepared by aseptic processing and sterilized before medical use. The sterilization method (wet or dry heat, radiation, or chemical treatment) should not cause structural changes or lead to chain scission, cross-linking or a significant alteration in mechanical properties.⁷⁹ 

Despite their great potential as biomaterials, currently only a small number of polymers have been administrated in the human body and an even smaller subset of them has been clinically validated for systematic administration. Examples of approved water-soluble or amphiphilic neutral polymers include PEG,^27,28  poly(vinylpyrrolidone) (PVP) and its copolymers,⁸⁰  copolymers of N-(2-hydroxypropyl)methacrylamide (PHPMA),⁸¹  and poly(ethylene oxide)-b-poly(propylene oxide)-b-poly (ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic®).⁸²  These polymers have been utilized in a broad range of applications including preparation of soluble polymer–drug conjugates (PHPMA, PEG), surface modification of proteins, liposomes and nanoparticles (PEG, PHPMA, Pluronic®) and the preparation of micellar drug formulations (Pluronic®). Examples of clinically validated water-insoluble, biodegradable polymers include PLGA,^83–85  poly(orthoesters) (POE),⁸⁶  and polyisohexylcyanoacrylate (PIHCA).⁸⁷  These polymers have been used for the preparation of nanoparticles, biodegradable implants and viscous injectable materials. In addition, the amphiphilic poly(styrene-co-maleic acid) copolymer conjugated with neocarzinostatin (SMANCS) dissolved in lipid contrast medium Lipiodol has proven effective in several clinical trials for the treatment of cancer.⁸⁸

In fact, summarized in few words, the ultimate success of a biomaterial is determined by the ability to tailor its properties in order to satisfy a given set of chemical, morphological and biological criteria. Even so, biomaterial selection is still a complicated task, because many of those requirements remain unknown until the models are tested in vivo. Advances in synthetic methods, characterization tools and increasing the understanding of in vivo cell biology, are likely to lead to new functional materials with enhanced biological activity, fewer side effects, and improved therapies and diagnostics.