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Introduction

Natural and synthetic polymeric materials offer many possibilities for the design and application of controlled drug delivery systems (DDS). The polymers provide bioresorbable supports for a number of bioactive compounds from small molecules with specific pharmacological activity to biomacromolecules, such as enzymes, hormones and growth factors. These prospects are based on the dynamic molecular characteristics of high molecular weight polymer chains and the supramolecular nature of the association of macromolecular chains with specific bioactive agents. The dynamics and movement of chain segments and monomeric sequences are two important characteristics to build bioactive systems into a biomimetic platform that provides alternatives to the classical application of bioactive ­compounds and specific drugs.

Basically, two approaches for polymeric chains to participate in dynamic and reversible processes of making bonds between macromolecules and of the monomeric functional components with the bioactive compounds. These interactions are established through physically dynamic noncovalent bonds by ionic and polar functional groups, that give rise to well known supramolecular structures, or by chemically dynamic situations through reversible covalent bonds that are important in the design and application of “targeting” systems and the development of “polymer drugs” which have open a very active discipline known as “polymer therapeutics” [1]. One of the most important characteristics of the systems based on physical supramolecular structures, or dynamic and reversible chemical blocks, is that all the systems have to offer the possibility to avoid the accumulation of the macromolecular support in the body, by the application of polymers that, after a controlled time interval, would bio-degrade or solubilize in physiological conditions to facilitate the clearance of nonbioactive residues in the body. To achieve this challenge, the application of biodegradable polymeric systems, it is necessary that biogradtion gives nontoxic low molecular weight products, or soluble polymer chains of the adequate molecular size, to be cleared by the normal ­metabolic route from the body. In this sense, the application of biodegradable or resorbable polymeric hydrogels becomes one of the most important concepts to be considered for the design and application of controlled release systems and polymer drugs.

From a physical point of view, the association of polymer–polymer, polymer–drug, or polymer–bioactive components can be established by means of: electrostatic interactions, hydrogen bonding, donor–acceptor, van der Waals forces, or even metal–ion coordination. There are clear examples of supramolecular systems in the living tissues constituted by this mechanism and even it is the basis for metabolic functions, cell growth and proliferation, or the pharmacological action of a great number of drugs. The chemical approach gives excellent opportunities for the design and development of bioactive polymer systems and polymer drugs, with a lot of possibilities for the modulation and control of the targeting of these very interesting bioactive systems. Reversible chemical reactions of functional groups present in monomeric components, building blocks in polymer chains, linear polymerization with control of the molecular weight and molecular weight distribution, and crosslinking, are some of the possibilities of this very wide and attractive approach for the development of bioactive macromolecules of very high interest in “polymer therapeutics.” The reversible chemical reactions are very frequent in nature and a single example is the reversible crosslinking of proteins based on disulfure links from aminoacid components of the macromolecular chains.

Bioactive degradable hydrogels based on natural macromolecules (polysaccharides, polypeptides, proteins), or designed with synthetic or biohybrid polymer systems, offer a wide range of possibilities and actuations in a biomimetic way, with the advantage of the precise selection of components not only from a chemical and structural point of view, but also from morphological considerations, the modulation of the resorption kinetics and mechanism, with the corresponding control of the targeting to the active local point and the release of the pharmacologically or bioactive main component.

Nature has developed evolutionary processes with elegant strategies for the specific application of bioactive agents, most of them are based on very well known macromolecules and supramolecular assemblies. Clear examples of that are; proteins like insulin, polysaccharides as hyaluronic acid or glucosaminoglicans such as chondroitin sulfate. Therefore, nature can be considered as the best model for the development of new and advanced targeting and DDS to be applied in the frame of new strategies in nanomedicine and therapeutic actions with high efficacy, local action, and reduced toxicity.

The current strategies for the development of systems for targeting and controlled release of specific drugs and bioactive molecules (growth factors, hormones, antioxidants, and cell activators for regenerative medicine) are based on the design and development of biodegradable hydrogels.

The Nature of Biodegradable Hydrogels

Hydrogels are three-dimensional, crosslinked physical or chemical networks of water-soluble polymers, that encompass a wide range of chemical compositions and bulk physical properties. Hydrogels can be classified according to the interactions between components into physical or chemical gels.

Polymers with very different chemical structures as multivalent polymers, branched polymers, graft polymers, dendrimers, dendronized polymers, block copolymers, and stars [1] have been used for the preparation of biodegradable hydrogels for DDS (Fig. 1).

Fig. 1.
figure 1

Polymer structures used in the synthesis of hydrogels for drug delivery.

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Hydrogels can be prepared with natural or synthetic polymers. In general, natural macromolecules present inherent biocompatibility, biodegradability, and biological moieties that support cellular activities. However, they usually do not provide sufficient mechanical properties and may contain pathogens or evoke immune/inflammatory responses. On the other hand, synthetic hydrogels present well-defined structures that can be manipulated to obtain biodegradability and a specific functionality.

Physical Hydrogels

Hydrogels are “physical” gels when the networks are held together by the growth of physically connected aggregates (Fig. 2). Depending on the nature of each gelling system, the junctions may be molecular entanglements, ordered crystalline regions, phase-separated microdomains, and/or secondary forces including ionic, H-bonding, or hydrophobic forces. Physical hydrogels are not homogeneous, since clusters of molecular entanglements, or hydrophobically or ionically associated domains, can create inhomogeneities. The common disadvantage of physical crosslinking is that the gels formed are unstable and may disintegrate rapidly and unpredictably.

Fig. 2.
figure 2

Interactions of specific functional groups in the formation of physical gels.

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Hydrophobic Interactions Hydrogels

Polymers with hydrophobic domains can crosslink in aqueous environments via reverse thermal gelation (sol–gel transition). The gelation occurs when a gelator (the hydrophobic segment) is coupled to the hydrophilic polymer segment of an amphiphilic polymer. These polymers are water soluble at low temperatures. As the temperature is increased the hydrophobic domains aggregate to minimize the hydrophobic surface area, reducing the amount of structured water surrounding the hydrophobic domains and maximizing the solvent entropy (Fig. 3). The temperature at which gelation occurs depends on the concentration of the polymer, the length of the hydrophobic block, and the chemical structure of the polymer. There is great versatility in composition, structure, and molecular weight of the synthetic polymers. Poly(ethylene glycol) (PEG) is one of the simplest and most used in the preparation of physical hydrogels.

Fig. 3.
figure 3

Sol–gel transition of A-B-A block copolymers.

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A series of interesting biodegradable and biocompatible ABA-type triblock copolymers (PEG–PLLA–PEG) as thermo-sensitive hydrogels was developed [2]. Their sol–gel transitions were easily manipulated by changing the biodegradable block length; by increasing the PLLA block length, the aggregation tendency was increased to provide a lower critical gelation concentration (CGC) with steeper sol–gel transition curves. The system was designed for delivery of high Mw or low Mw hydrophobic protein drugs which have a low diffusion co-efficient. These PEG–PLLA–PEG systems and their degradation products are known to be biocompatible and pharmacologically inactive, so there is no need for removal of an implanted delivery system.

Other ABA copolymers have been synthesized using shorter PEG (Mw < 750) and PLGA blocks [3]. This system showed gelation transitions near physiological temperature. These are tunable by tailoring the block length and compositions. The “in vitro” drug release behavior of PEG–PLGA–PEG hydrogels was evaluated by using ketoprofen and spirolactone as ionizable and nonionizable model drugs, respectively [4]. The release of ketoprofen was first-order release over 2 weeks, indicating a diffusion controlled mechanism. In contrast, the release of spironolactone exhibited an S-shaped release profile over 2 months, suggesting a diffusion-controlled process followed by a degradation-dominated process.

PLGA–PEG–PLGA BAB-type triblock copolymers were synthesis using hexamethylene diisocyanate. Compared with PEG–PLGA–PEG, these copolymers have a lower sol–gel transition temperature that is influenced by the block length and composition [5].

ReGel® is a commercial biodegradable PLGA–PEG–PLGA (1,500–1,000–1,500) hydrogels. ReGel® drug release and degradation is a diffusion-controlled during the initial 2 weeks followed by a combined diffusion/degradation controlled process within a 4-week degradation time [6].

PLGA undergoes rapid degradation in the block copolymer releasing acidic products leading to an environment in the hydrogels, which is deleterious to bioactive proteins and to cells. Poly(η-caprolactone) was considered an alternative to hydrophobic blocks that release fewer acidic products during the degradation, but suffers from extremely slow degradation rates. New thermosensitive biodegradable triblock copolymers, based on PEG–[poly(β-caprolactone-co-glycolide)]–PEG, (PEG–[PCL-co-GA]–PEG), were prepared and characterized. The glycolide was incorporated into the hydrophobic block to avoid PCL crystallization and enhance biodegradation [7].

Pluronic® (BASF) and Poloxamer® (ICI) are block copolymers based on PEO–PPO sequences and are widely used in pharmaceutical systems. These systems have sol–gel transitions below or close to the physiological temperature as high as 50°C by tailoring the hydrophobic–hydrophilic balance which changes the three-dimensional packing of the micelles formed. Thermal transitions depend on polymer composition and solution concentration; therefore, these polymers are attractive for controlled release injectable formulations [8]. However, their applications in DDS are limited by their lack of biodegradability. Sub-sequently, a family of degradable pentablock copolymers, composed of Pluronic F87 flanked by two short biodegradable polyester blocks (PLA or PCL) [9, 10] that provided controlled release without an initial burst release, were prepared by these authors.

A high strength degradable hydrogels, based on an enantiomeric mixture of starburst triblock copolymers consisting of an 8-arm PEG and poly(l-lactide) (PLLA) or poly(d-lactide) (PDLA), was synthesized [11]. This hydrogels was stable after cooling below the transition temperature due to the formation of stable stereo complexes. The combination of rapid temperature-triggered irreversible hydrogels formation, high-mechanical strength, and degradation behavior renders this polymer suitable for injectable biomedical applications.

Synthetic block copolypeptides incorporating hydrophobic and hydrophilic segments, which are thermosensitive and present similar behavior to Pluronics®, were developed [12, 13]. However, the sol–gel transition took place at lower concentrations since part of the molecule adopts an α-helix conformation that facilitates gelation. Bellomo et al. [14] prepared synthetic vesicles based on amphiphilic copolypeptides with a high degree of architectural control. The hydrophilic block, made of L-lycine was grafted with water soluble etheline gylcol to make the hydrophobic lycine block consistant with L-leucine. Each block presented a different secondary structure: poly(l-lysine), ionized polyelectrolyte, presented a stretched linear configuration and poly(l-leucine) an α-helix secondary structure, which produced a dramatic effect in the overall structure.

Reversible physical networks based on PAA and poly(2-vinylpyridine) triblock copolymers (PAA–P2VP–PAA) that have an isoelectric point at ∼5.5 and form a gels at pH ∼3.4 were prepared by Sfica and Tsitsilians [15]. When the pH was increased near the isoelectric point the polyampholyte. Precipitated, and as the pH was further increased, the polymer redissolved due to the formation of micelles with P2VP as core and charged PAA chains as the shell.

Supramolecular structures based on amphiphilic block copolymers and cyclodextrins (CD) also formed interesting controlled DDS [16]. Supramolecular hydrogels based on the self-assembly of the inclusion complexes between CDs with biodegradable block copolymers were injectable DDS for macromolecular drugs. The CD-containing cationic polymers were described as “gene carriers” with reduced toxicity compared non-CD-containing polymer counterparts [16].

Dendritic structures provided an ideal platform for drug delivery. The advantages of these structures were the highly branched nanoscale architecture and the many surface reactive groups; these provided drug targeting and high drug payloads. The cytotoxicity and cell permeability of dendrimers was found to increase with increasing generation and concentration [17]. Many of their adverse effects were reduced by conjugation of poly(ethylene glycol) (PEG) to their surface. Conjugated PEG dendrimers reduced cytotoxicity and immunogenicity and also provided dendrimers with excellent solubility, favorable pharmacokinetic, and tissue biodistribution [18]. For example, the carbonyl group of ibuprofen formed electrostatic complexes with the PAMAM dendrimer amine groups. The complexed drug entered A549 cells more rapidly than pure drug, indicating that dendrimers may effectively carry complexed drugs inside cells [19].

Ionic Interaction Hydrogels

A physical “ionotropic” hydrogels is formed when a polyelectrolyte is combined with a multivalent ion of opposite charge. When polyelectrolytes of opposite charges are mixed, they may form a gels or precipitate depending on: the concentrations, the ionic strength, and pH of the solution. The products of ion-crosslinked systems are known as complex coacervates, polyion complexes, or polyelectrolyte complexes. Complex coacervates and polyion complex hydrogels are attractive as tissue engineering matrices as these physical gels can form biospecific recognitions. All these interactions are reversible and can be easily disrupted by simple changes in physical conditions, such as pH or ionic strength.

A 5-aminosalycilic acid colon-specific delivery system is based on chitosan-Ca2+-alginate by spray drying and followed by ionotropic gelation/polyelectrolyte complexation [20]. The highly cooperative ionic bonds between the positively charged chitosan and negatively charged alginate, the main driven force binding of the intermolecular and intramolecular hydrogen bonds and hydrophobic forces between the drug and the polymers, increased the mechanical strength of the gels network and decreased its porosity/permeability. “In vivo,” these microspheres have been localized in the colon of Wistar male rats that were previously induced with colitis.

Biodegradable nanoparticles that solidify “in situ” upon injection into isotonic phosphate buffered saline (PBS) with no additional initiators were developed [21]. These nanoparticles are prepared from different amine-modified polyesters: diethylaminopropyl-amine-poly(vinylalcohol)-g-poly(lactide-co-glycolide) (DEAPA (68)-PVA-g-PLGA(1:20)), diethylaminoethyl-amine-PVA-g-PLGA (DEAEA(33)-PVA-g-PLGA(1:20)), and dimethylaminopropyl-amine-PVAL-g-PLGA (DMAPA(33)-PVA-g-PLGA(1:20)). The “in situ” depots are formed by ion-mediated aggregation. The “in vitro” insulin release from these systems gave good results [21].

Microspheres can also be formed croslinking hydrogels by ionic interactions. An example is the preparation of microspheres by polymerization of acrylic acid in the presence of chitosan [22]. This kind of systems have been used as meclofenamic acid delivery systems. The release of this drug was controlled by the solubility of the drug and not by the swelling of the polymeric matrix at different pH. A constant release was observed during 2–4 weeks. The particles were biocompatible and bioresorbable by living tissues based on “in vivo” tests [23].

Hydrogen Bonded Hydrogels

Hydrogen bonded hydrogels as injectable hydrogels are formulated by mixing two or more natural polymers that exhibit rheological synergism. These blends are more gels-like than those of the individual polymers due to the extensive hydrogen bonding interactions. However, the hydrogen bonds are relatively weak and easily disrupted by shear forces within the needle. Hydrogen bonded natural polymers, such as gelatine-agar [24] and hyaluronic acid-methylcellulose [25], exhibit excellent biocompatibility; however, they are often diluted and dispersed in few hours due to an influx of water from surrounding tissues; consequently, their use is restricted to relatively short-acting drug release requirements.

New bioactive dressings based on chitosan-lactate (ChL) and PVA loaded with nitrofurazone for wound healing have been developed with good results both “in vitro” and “in vivo” [23]. Hydrogels were formed by the phase inversion technique after blending solutions of both polymers. ChL blended with PVA improved hemocompatibility and mechanical properties of the synthetic PVA, maintaining the bioresorbable character of this kind of hydrogels [23].

Chemically Bonded Hydrogels

The most common hydrogels are those obtained by chemical crosslinking of hydrophilic molecules to form a network. Covalent-linkages allow the material to swell without loss of structural integrity. Chemical hydrogels usually contain regions of high crosslink density with low water swelling, called “clusters,” dispersed within regions of low crosslink density with high swelling. This pattern could be due to hydrophobic aggregation of crosslinking agents, leading to high crosslink density clusters [26]. In some cases, temperature and solids concentration phase separation can occur during gelation to form water-filled “voids” and/or “macropores.”

Small-molecule crosslinkers can be used to produce “in situ” crosslinked hydrogels. For example, human serum albumin was crosslinked with the activated ester of tartaric acid to create a tissue adhesive hydrogels for primaquine® delivery and encapsulation of hepatocytes [27]. Several types of linkages with polymers with reactive functional groups can be used, depending on the rate of crosslinking and biodegradability needed. For example, a mixture of thiol-modified heparin and thiol-modified hyaluronic acid gels with PEG diacrylate forms a hydrogels that prolongs the release of bFGF in vivo [28].

N-isopropylacrylamide (NIPAM)-based hydrogels are extensively used as chemical gels [29, 30]. Thermosensitive NIPAM-based hydrogels were prepared using the biodegradable pseudo-peptide crosslinker DMTLT (a tri-molecular adduct of tyrosine, lysine, tyrosine) [31]. The volume phase transition temperature and the morphology of the gels were modulated by the amount of DMTLT. In aqueous media, these hydrogels exhibited a well-defined pulsate behavior in swelling and the release of benzoic acid and dextran as models of ionizable ­molecules and noionizable macromolecules, respectively.

Summary

Biomimetic hydrophilic and amphipilic hydrogels, based on combinations of biodegradable and/or resorbable biocompatible polymeric systems, provide excellent opportunities for controlled release and targeting of specific drugs and bioactive compounds. The ­problems with healing wounds of compromised patients are now well addressed, with good response, by the application of new polymeric hydrogels with bio-adhesive properties and controlled delivery mechanisms, thanks to the combination of effects associated to intermolecular interactions of polymers and polymer–drugs or polymer–bioactive compounds interactions. Smart polymers that are sensitive to the physiological conditions in a specific application (dermal, eyes, connective tissue) are of interest with the new and advanced hydrogels formulations being developed for clinical applications.

Hydrogels in bioactive scaffolds for “in situ” tissue regeneration are being developed by companies around the world with opportunities to advance the regeneration of tissues and organs. Applications in regenerative processes for soft tissues and cartilage or meniscus are good examples of the potential and relevant position of this kind of polymeric system in the advanced concepts of regenerative medicine.