Biopolymer based hydrogels are three-dimensional physically or chemically crosslinked polymeric networks based on natural polymers, with an intrinsic hydrophilic character due to their functional groups. They display high water content, softness, flexibility, permeability, and biocompatibility and possess a very high affinity for biological fluids. These properties resemble those of many soft living tissues, which opens up many opportunities in the biomedical field. In this regard, hydrogels provide fine systems for drug delivery and sustained release of drugs. Moreover, biopolymer based hydrogels can be applied as coatings on medical implants in order to enhance the biocompatibility of the implants and to prevent medical conditions. In this chapter we review the latest achievements concerning the use of biopolymeric physical and chemically crosslinked hydrogels as well as hydrogel coatings as sustained drug release platforms.
- sustained release
- drug delivery
- hydrogel coating
Gels can be defined as three-dimensional cross-linked polymeric networks which swollen in contact with a liquid. When the polymers forming the gel contain mainly hydrophilic functional groups, the liquid that causes the swelling is water, and the gel is called hydrogel . Biopolymers are often used for the synthesis of hydrogels as the natural composition of the polymer leads to extremely high biocompatibility and potential applications in the biomedical field .
Hydrogels can be classified as physical hydrogels when the properties of the gel depend on chain entanglements and other interactions, mainly hydrogen bonds or hydrophobic interactions . In this case, properties are highly dependent on chain molecular weight as well as concentration, as mobility of the chains modifies the structure of the hydrogel and therefore its physical properties. Water temperature, salt content, and pH can also affect the mobility of the chains and interactions and must be controlled .
Chemically crosslinked hydrogels present a much more stable structure than physical hydrogels. In chemical hydrogels, the polymeric chains are covalently bonded using one or more crosslinking agents, using a chemical process . In general, crosslinked hydrogels are less biocompatible than physical hydrogels, but this is compensated by other advantages: cross-linked hydrogels are insoluble, more stable, and rheological properties such as elasticity or viscosity, their pore size, and their degradation rate can be more optimized than with physical hydrogels.
Hydrogels can present different physical forms: from macrogels to micro and nanogels, which are particulate systems with similar chemical structure but different macroscopic size; implantable gels, with strong physical properties, or injectable gels, more fluids or composed of nano-microparticles which can pass through a needle; hydrogel coatings, where hydrogel nano or microlayer is immobilized on a surface; thermoresponsive or pH-responsive gels, where a trigger modulates the sol–gel properties, can be easily injected in a liquid form before gelation in physiological conditions .
Physical properties of physically and chemically crosslinked hydrogels, are similar to several soft biological tissues, and therefore they can be used as substitutes or supplements when the biological function of these soft tissues is compromised. Such hydrogels have been widely used as medical devices for different applications: in traumatology, as substitute or supplement of synovial fluid in osteoarthritis; in ophthalmology, as a substitute of aqueous humor during in cataract surgery; in esthetics and reconstructive surgery, as dermal fillers for rid correction and lipoatrophy for patients with VIH; in wound healing, as wound dressings to promote regeneration and healing of wounds .
The biomedical use of the hydrogels can be expanded by the employ of the hydrogels as a sustained release system. Concerning this the controlled release of pharmaceutical ingredients leads to important advantages as a control of the biodisponibility, dose control, local delivery and less side effects . This chapter aims to cover a general overview concerning the sustained drug release from hydrogels and hydrogel coatings. In that regard,
2. Mechanism of drug release form hydrogels
The release of drugs from hydrogels can be achieved by different mechanisms such as swelling/deswelling, diffusion, and chemical mechanism. As previously mentioned, hydrogels are three-dimensional crosslinked polymeric networks that swelled in the presence of water. The crosslink can be physical (hydrophobic interactions, electrostatic interactions and hydrogen bonding) or chemical (covalent bonding) and is responsible of the network structure of the hydrogel. Such networks display open spaces, the size of which is referred to as the mesh size of the hydrogel . Importantly, the mesh size of the hydrogels is one of the main parameters that affect how drugs diffuse through the hydrogel network, being dependent on polymer and crosslinker concentrations, as well as external stimuli. The gelation of hydrogels by polymerization means leads to network irregularities and polymer polydispersity upon formation, and as a result, the mesh size is usually heterogeneous. A number of approaches exist to determine the mesh size .
When the mesh is larger than the drug (rmesh/rdrug > 1), the drug release process is dominated by diffusion. Small drug molecules migrate freely through the network, and diffusion is largely independent of the mesh size. The diffusivity, D, in this situation depends on the radius of the drug molecule (rdrug) and the viscosity of the solution (η) via the Stokes–Einstein equation Eq. (1) :
where R is the gas constant and T is the absolute temperature.
When the mesh size is close to the drug size (rmesh/rdrug ≈ 1), the effect of steric hindrance on drug diffusion becomes relevant. Finally, for an extremely small mesh size and/or very large drug molecules (rmesh/rdrug < 1), strong steric hindrance immobilizes the drugs and it remains physically entrapped inside the network, unless the network degrades or the mesh size expands in response for example, to external stimuli.
Several methods accompanied by mathematical model development have been created in parallel to hydrogel technology, in order to predict drug release from the network. The drug release fitting models (i.e. the zero order equation; the first order equation; the Higuchi’s equation; the Korsmeyer-Peppas’ equation; the Hixon-Crowell’s equation, the Weibull equation, among others) are the most abundant, however, they are not predictive but simple mathematical fitting equations. In the last years, mechanistic and statistical models are growing quite fast. Mechanistic models combining the mass transport with the system mechanics developed with a “fully coupled” approach considers the influence of the mass transport on the mechanics as well as the opposite, which makes this approach the only candidate to produce reliable first-principle models.
Statistical models, are receiving a lot of attention due to the consensus of the regulatory authority and the possibility to predict the hydrogels behavior, in the analyzed design space, regardless the complicate phenomenology, with quick and inexpensive experimental designs . Recently, Wu and Brazel developed a method for the simulation of water uptake profile and drug release from homogeneous hydrogels. This model successfully predicted the initial burst release observed experimentally . Sheth et al. developed a mathematical and computational model using time snapshots of diffusivity and hydrogel geometry data measured experimentally as inputs to predict release profiles of two model proteins of varying molecular weights from degradable hydrogels .
3. Drug release from physical hydrogels
Physical hydrogels are those formed by reversible and dynamic crosslinks grounded on noncovalent interactions. In this regard the network of physical hydrogels is reversibly held together by molecular entanglements, resulting from a dynamic competition between pro-assembly forces (for example, hydrophobic interactions, attractive electrostatic forces and hydrogen bonding) and anti-assembly forces (for example, solvation and electrostatic repulsion . These interactions that occur in this type of hydrogels are usually weak. However, they are numerous and contribute to the presence of complex behaviors.
Polyampholytes may also be used to construct physical hydrogels, with randomly dispersed cationic and anionic groups. The randomness leads to a wide distribution of strengths: The strong bonds serve as structural crosslinks, imparting elasticity, whereas the weak bonds reversibly break and re-form, dissipating energy. Consequently, physical hydrogels have reversible liquid to solid transition, also called sol–gel transition, in response to different changes in environmental conditions such as temperature, ionic strength, pH, or others . Since the interactions depend significantly on external stimuli, they allow hydrogels to be highly versatile concerning the environment, unlike covalently bonded materials .
Physical hydrogels can be engineered to undergo spontaneous biodegradation under physiological conditions, which constitutes another way of controlling the release of active molecules . Degradation is typically mediated by hydrolysis [17, 18] or enzyme activity . The erosion or loss of polymer mass through degradation, can take place simultaneously in the bulk or on the surface of the hydrogel. For a variety of hydrogels, the bulk and surface erosion can be tuned to obtain desirable release kinetics ranging from weeks to months. Bulk erosion occurs because of the permeability to water or degrading enzymes when the rate of diffusion of these agents is rapid compared to the rate of bond degradation. Surface erosion, in contrast, results when the rate of bond breakage is more rapid than the rate of enzyme or water diffusion from the exterior into the bulk of the gel .
Representatives of reversible physical hydrogels are the shear-thinning hydrogels which flow like low-viscosity fluids under shear stress during injection, but quickly recover their initial stiffness after removal of shear stress in the body . Alginate hydrogels are shear-thinning, formed via electrostatic interactions between alginate and multivalent cations (for example, calcium and zinc). They can be readily injected via a needle after gelation in a syringe and have been used to achieve sustained local delivery of bioactive vascular endothelial growth factor (VEGF) in ischemic murine hindlimbs for 15 days [20, 21].
3.1 Peptide based physical hydrogels
Another example of physical hydrogels forming materials are the self-assembling peptide systems, where amino acid-based chains undergo the sol–gel transition without the need of any chemical crosslinking agent. This property makes them useful materials to safely in situ encapsulate living cells or sensitive drugs, among others. In addition, this peptide-driven self-assembly into physical hydrogels is highly specific, sourced mainly by the biorecognition of peptide segments scattered among the macromolecular chains. They form dynamic well-defined, hierarchically organized 3D structures with reversibility of the assembly and disassembly processes . Another example are elastin-like polypeptides cross-linked via electrostatic interactions between their cationic lysine residues and anionic organophosphorus cross-linkers . Non-covalent interactions between heparin and heparin-binding peptides and proteins can also be used to form hydrogels for growth factor delivery [24, 25].
Peptide self-assembly can also be achieved by taking advantage of interactions between metal cations and amino acid residues of the peptides. This was demonstrated with gelation of a β-sheet-rich fibrillar hydrogel with zinc ions .
3.2 Chitosan based physical hydrogels
Additional interesting example of physical hydrogels for drug release applications are pectin-chitosan hydrogels, which showed to be thermo-reversible and capable of prolonging the release of three different model hydrophobic drugs: mesalamin, curcumin and progesterone. In vitro drug-release studies revealed that lower percentage of pectin in the hydrogel led to slower release rates owing to smaller mesh size arising from stronger interactions between the polyelectrolytes. Also, the release was slower when the total polymer concentration was higher. Finally, a slower release in PBS solution compared to HCl solution was attributed to the fact that at pH 7.4, both polymers are charged, with strong electrostatic forces and consequently, smaller mesh size. At the molecular scale, the polymer chains can possess abundant binding sites for the drugs. DSC and FTIR analysis exhibited some interactions between the drugs and both chitosan and pectin that can contribute to the prolonged release of the drugs . Another in situ-gelling hydrogel was formed with a polyelectrolyte complex, which showed a sustained release of insulin and avidin proteins .
4. Drug release from chemically cross-linked hydrogels
Crosslinking of biopolymers provide a stable and non-soluble biomaterial which preserves the properties of the original biopolymer and displays a longer durability. Consequently, the half-life time of the hydrogels is increased when performing its biological application .
Usually, biopolymer crosslinking can be accomplished in two ways: by direct addition of a cross-linking agent followed by formation of a the three-dimensional (3D) network, or by chemical modification of the biopolymer chains with functional groups suitable for crosslinking with a compatible cross-linker. The first approach takes advance of the functional groups already present in the biopolymer, typically amine (NH2), hydroxyl (-OH), carboxylic acid (-COOH), amide (-CONH-, -CONH2), thiol (-SH) or sulfate (-SO3H) groups . Examples of cross-linkers are dialdehyde derivatives, NH2-PEG-NH2 molecules, COOH-PEG-COOH derivatives, diglycidyl ether compounds, vinyl sulfone groups, etc. These agents cross-link through Michael-type addition, thiol exchange/disulfide cross-linking or Schiff-base processes among others . In some case the addition of coupling agents such as carbodiimides derivatives, N-hydroxysuccinimide (NHS) or N-hydroxybenzo triazole (HOBt), is required for the cross-linking. In the second approach new active functionalities are created in the biopolymer [31, 32] which are appropriate for a broad range of cross-linking processes such as azide–alkyne cycloadditions, Diels–Alder reactions, ultraviolet (UV) photoinitiated crosslinking, (meth)acrylation reactions [5, 32]. Examples of cross-linkers are oxanorbornadiene, cyclooctyne, maleimide, trans-cyclooctene, norbornene, PEG-di(meth)acrylates among others.
The crosslinking of biopolymers produces hydrogels with elastic and deformable structures and great topochemical accessibility which is able to accommodate different kind of active molecules, such as drugs, for sustained release (Figure 1).
4.1 Chitosan based chemically crosslinked hydrogels
Chitosan (CHI) is a linear polysaccharide formed by arbitrarily allocated β-(1 → 4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). Chitosan is one of the most versatile biopolymers due to its unique properties: biodegradability, biocompatibility, non-toxicity, antioxidant, anti-inflammatory, antifungal, and antibacterial “contact killing” . Therefore the applicability of this polysaccharide extends to a wide range of various biomedical areas, such as cosmetics, drug delivery, and tissue engineering, among others .
In this regard a covalently crosslinked chitosan hydrogel was produced Diels Alder reaction of furan and maleimide functionalized CHI. The resulting biopolymer held the typical pH sensitivity and antibacterial properties of non-functionalized CHI. The drug delivery capabilities of this system were evaluated with model drug antibiotic chloramphenicol (ClPh). Drug release experiment did not show an initial burst, which indicated that the ClPh was successfully encapsulated, whereas it displayed a sustained delivery of the drug with a complete release of the total amount of drug loaded (2.61 ± 0.036 mg ClPh/g hydrogel) after 4 hours .
CHI was also crosslinked with genipin (GP) to obtain biocompatible, antibacterial and anti-inflammatory hydrogels with wound healing properties. Sustained release of acetylsalicylic acid (ASA), cefuroxime (CFX), tetracycline (TCN) and amoxicillin (AMX) from the hydrogels displayed a Pharmacologic Half Life t1/2 values of 88 h, 62 h, 135 h, and 240 h for ASA, CFX, TCN and AMX respectively. These antibiotic releases generated antibacterial activity against
Moreover, dialdehyde-β-cyclodextrin (DA-β-CD) crosslinked carboxymethyl chitosan (CMCS) hydrogels were prepared from carboxymethyl chitosan (CMCS) and periodate oxidized β-CD. Phenolphthalein (PhP), a formerly used laxative agent,  was selected as a model molecule to investigate the drug loading and sustained release capabilities of such hydrogels. PhP release results show that increasing crosslinking rate between DA-β-CD and CMCS delays the drug liberation process. On the other hand, DA-β-CD/CMCS system displays faster releases, with a 50% release in 2 h and about 90% within 12 h, compared to CMCS crosslinked with glyoxal dialdehyde which only releases 19% of PhP after 24 h .
CHI based hydrogels (N-succinyl chitosan-g-Poly(acrylamide-co-acrylic acid) were synthesized by free radical mediated cross-linking of N-succinyl chitosan, acrylamide and acrylic acid . Drug delivery capabilities of the system were tested by encapsulation of theophylline, a phosphodiesterase inhibiting drug used for the treatment of respiratory diseases. The drug release experiments showed a pH dependent behavior. In this regard, at pH 1.2 the theophylline released rate was found to be between 14 and 24% whereas at pH 7.4 the release of the drug reached 67–93%. CHI itself has been used as a cross-linking agent for poly(acrylic acid). The resulting hydrogels display pH sensitive properties that have been exploited to control the release of antibiotic amoxicillin and anti-inflammatory drug meloxicam. Concerning this, the release rates of these molecules rise with increasing pH due to the disruption of hydrogen bonds between the hydrogel components and the drugs. As a result 30%, ∼60% and ∼80% of amoxicillin is released after 800 min at pH 1.2, 6.8 and 7.4, respectively. The corresponding release data for meloxicam are ∼20%, ∼70% and ∼90% at pH 1.2, 6.8 and 7.4, respectively .
4.2 Hyaluronic acid based chemically cross-linked hydrogels
Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan constituted by repeating disaccharide β-1,4-D-glucuronic acid–β-1,3 N-acetyl-D-glucosamine units that form hydrogels in aqueous solutions. This naturally occurring polysaccharide is found in connective tissues, skin, and synovial joint fluids of the human body. HA displays bio-functionality, biocompatibility, and physicochemical properties, such as viscoelasticity and high-water retention. As a result hyaluronic acid is used for the treatment of dry eye disease, dermatological conditions as well as a as a viscosupplement for the treatment of osteoarthritis .
Biocompatible antibacterial hydrogels of HA were synthetized by crosslinking HA solution with divinyl sulfone (DVS) followed by loading with antibiotic molecules. This way cefuroxime (CFX), tetracycline (TCN) and amoxicillin (AMX) loaded hydrogels displayed in vitro antibacterial activity against S. aureus. The antibacterial properties of the hydrogels were synergically enhanced by merging antibiotics with anti-inflammatory agent acetyl salicylic acid (ASA). Consequently it was observed an increase in the log10 reduction value (R) from 3.2, in the absence of ASA, to R 5.55 when TCN or CFX were combined with ASA .
Hyaluronic acid was crosslinked with 1,4-butanediol diglycidyl ether (BDDE) and loaded with quetiapine (QTP), an antipsychotic drug, and quercetin (QCT), a hyaluronidase (HAase) inhibitor that decreases the biodegradation of HA. Subcutaneous injection in rats of the system showed that the cHA hydrogel with QCT exhibited a lower maximum QTP concentration (Cmax. 782.6 ± 174.4 ng/mL) and longer half-life (t1/2 23.5 ± 2.7 h) and mean residence time values (MRT 30.9 ± 3.9 h) compared to the hydrogel without QCT (Cmax. 1827.6 ± 481.3 ng/mL, t1/2 13.4 ± 4.9 h, MRT 14.3 ± 4.8 h). These results demonstrated that HAase containing HA hydrogels are suitable systems for sustained drug delivery applications .
A thiol functionalized hyaluronic acid HA-SH was used, together with DMSO, for the fabrication of HA-SS-HA hydrogels. This system was loaded with antitumoral drugs such as doxorubicin (DOX), zinc phthalocyanine (ZnPc), and indocyanine green ICG, for implant post peritumoral administration. In vivo experiments validated that drug loaded hydrogel implant possessed satisfactory biocompatibility and succeeded in long term sustained release of drugs. As a result the system to ensured high tumor aggregation efficiency and adequate tumor suppression . Hyaluronic acid (HA) functionalized with thiol and hydrazide moieties has been combined with oxidized sodium alginate (ALG)to produced cross-linked hydrogels (HA/ALG). These materials display tunable physicochemical properties and drug release behavior as a function of the HA/ALG precursor concentration. In this regard for HA2/ALG2 (2% w/v), HA3/ALG3 (3% w/v) and HA4/ALG4 (4% w/v) the yield stress of hydrogels were 1724, 4349 and 5306 Pa, and the degradation percentage were about 64%, 51%, and 42% after 35 days incubation, respectively. Thus, in vitro cumulative release of Bovine serum albumin (BSA) for HA2/ALG2, HA3/ALG3 and HA4/ALG4 were 79%, 72%, and 69% respectively for a 20 day release assay .
Near-infrared (NIR) light-triggered and reactive oxygen species (ROS)-degradable hyaluronic acid hydrogels (HPTG) were synthesized through the formation of dynamic covalent acylhydrazone bonds. Such system was loaded with photosensitizer protophorphyrin IX (PpIX) and anticancer drug doxorubicin (DOX), to obtain a with light-tunable on-demand drug release for chemo-photodynamic therapy. In this regard NIR light irradiation generated ROS that induced the required degradation of hydrogel and subsequent on-demand DOX release for cascaded chemotherapy. In vivo imaging-guided antitumor study using 4 T1 tumor- mouse model demonstrated that the treatment of DOX-loaded HPTG with laser irradiation nearly accomplished the suppression of tumor growth without noticeable regrowth .
Tyramine functionalized HA solutions were combined silk fibroin (SF) to produce a series of HA/SF hydrogels for application in cartilage tissue engineering an and drug delivery. These hydrogels were loaded with Vanillic acid (VA) or Epimedin C (Epi C), both with anti-catabolic, anti-inflammatory and anabolic effects on human cartilage cells. Hydrogels with HA20/SF80 polymeric ratios displayed the longest and the most sustained release profile with 70.1% release of VA after 60 days of release assay and 54% release of Epi C after 7 days of release. Such behavior makes HA20/SF80 hydrogels a prospective material for the treatment of osteoarthritic joint conditions .
Polyethylene glycol (PEG)-HA was modified also with a small biologically active molecule, as dopamine, to fabricate a HD-PEG polymer. This polymer was crosslinked with α -cyclodextrin (α-CD) to afford a polypseudorotaxane supramolecular complex HD-PEG/α-CD. The system was loaded with poly(lactic-co-glycolic acid) (PLGA)/donepezil microspheres (PDM) in order to evaluate the drug delivery capabilities of the system. The released amounts of donepezil, a drug used for the treatment of mental conditions, reaches 39.9% and 56.7%, after 7 and 14 days respectively. These results demonstrate that the HD-PEG/α-CD/PDM system could be used for the subcutaneous injection of long acting donepezil . Similarly, poly(L-lactide-co-glycolide) (PLGA) – dexamethasone (DEX) nanoparticles PLGADEX were combined with crosslinked HA for drug release applications. In this case the chemical crosslinking occurred doubly, by mixing amino-hyaluronic acid and aldehyde-hyaluronic acid in the presence of genipin as a cross-linker agent. Drug delivery experiments showed full DEX release after 2 months for a HPLGADEX hydrogel .
Oxidized hyaluronic acid (OHA) was combined with carboxymethyl chitosan (CMC) via Schiff base reaction to fabricate a hydrogel (OHA-CMC) with antibacterial and hemostatic activities. The drug delivery potential of the system was exploited by encapsulating PLGA-PEG nanoparticles of curcumin (CNP) and epidermal growth factor (EGF) that afforded a OHA-CMC/CNP/EGF hydrogel. This system displayed outstanding anti-inflammatory, antioxidant and cell migration-promoting effects
Finally, HA has been used as well as a biopolymer for the fabrication of a 3D printable dual-network hydrogel with drug delivery capabilities. For that acrylamide-modified HA was synthesized and subsequently mixed with folic acid and Fe3+ to form a physical crosslinking network. Afterwards acrylamide residues were polymerized by ultraviolet radiation affording a material suitable for wound dressing with high elasticity and fatigue resistance. The drug delivery properties were investigated using acetylsalicylic acid (ASA) as a drug model and resulted in a pH responsive hydrogels with the sustained release of ASA over 300 hours .
4.3 Other chemically cross-linked biopolymers
Lignin is a sustainable biopolymer derived from lignol precursors that has been historically related to the paper industry. Hydrogels of hardwood lignin (TCA) have been synthesized through crosslinking with poly(ethylene) glycol diglycidyl ether (PEGDGE) and loaded with paracetamol for drug release applications. Here, decreasing amounts of crosslinker diminishes the interaction paracetamol - hydrogel network and, as a result, the release of paracetamol increases. In this regard, hydrogels produced with a lignin:PEGDGE 1:1 ratio displayed up to 30% of paracetamol release after 120 h assay. The release data follow a pseudo-Fickian behavior of diffusion when fitted to the Korsmeyer-Peppas model . Furthermore, lignin polymers have been mixed with cellulose to generate drug delivery systems. Mechanical and sustained release performances of these gels are tailored by varying the ratio of the precursors: cellulose, hardwood lignin (TCA), and epichlorohydrin (ECH) cross-linker. TCA containing hydrogels display the best release rate (>90%) for drug model paracetamol comparing to the pure cellulose hydrogels (~40%) after 7 hours of release experiment. This behavior is attributed to the lower affinity of paracetamol for lignin compared to cellulose .
Cellulose itself have been used for the fabrication of hydrogels with drug release properties. In this regard, carboxymethyl cellulose (CMC) functionalized with ꞵ-cyclodextrin and nucleic acids have been crosslinked by using of arylazopyrazoles (AAPs) and loaded with anti-cancer molecule Doxorubicin (DOX). The resulting hydrogel behaves as a functional matrix for the UV light mediated ON/OFF release DOX. Irradiation of the matrix provokes the photoisomerization of the trans-AAP to cis-AAP residues and the generation of the low-stiffness hydrogel that releases DOX. Therefore, the liberation of the DOX could be changed between ON and OFF states by oscillating the photoisomerization of the hydrogel by employing UV/Vis irradiation .
Xanthan is a heteropolysaccharide produced by fermentation from the bacteria
Casein is a proline-rich, open-structured protein found in raw milk. It displays high hydrophilicity, good biocompatibility and a lack of toxicity that makes of it a potential candidate for hydrogel development. Casein can be chemically cross-linked with enzymes such as microbial transglutaminase (MTG). This feature was utilized to produced crosslinked casein -γ-polyglutamic acid (PGA) hydrogels in 1/5 and 1/9 ratio. Drug release experiments showed that both composition displayed similar release rate values for aspirin (~ 100% after 10 h), while 1/9 hydrogels possessed a higher release rate for vitamin B12, ~100% after nearly 12 h versus ~20% for 1/5 casein/γ-PGA hydrogels .
5. Drug release from hydrogel-based bioactive coatings
Historically, the development of medical implants has been a great concern for biomedical community. Besides, their need has risen dramatically due to the increased number of surgical procedures that are predicted to be even higher in 2030 . Thus, improving the performance of implantable biomaterials has become a high-priority trend, which is reflected in the large number of research realized to successfully meet the upward demand .
Implantable medical devices (e. g. coronary stents, cardiac pacemakers, prostheses, insulin pumps) are classified in four main groups: ceramics , polymers , composites , and metals . Among them, metallic biomaterials as titanium and its alloys are of outmost interest thanks to their inert chemical and biological behavior
The use of these bioactive coatings entails the development of an improved version of bioactive materials that modulates biological systems response by the establishment of interactions with adjacent tissues and bones . Nevertheless, these coatings require the most suitable physicochemical, mechanical, and biological functionality for a successful implantation and integration so as not to produce any counterproductive disorder in humans . Therefore, it is imperative to develop functional bioactive coatings onto the surface of biomaterials (Figure 2, produced by the authors) that combine biocompatibility , antibacterial , anti-inflammatory , self-healing , wound healing , bone tissue engineering , and osseointegration  properties.
Such features can be incorporated onto the surface of biomaterials by the use of biopolymer-based coatings, mostly based on hyaluronic acid and chitosan . Moreover, these coatings acquire hydrogel-like three dimensional microstructure after crosslinking for bioactive agents delivery applications (Figure 3, produced by the authors). In such manner, bioactive properties that already possess biomaterials can be upgraded or even provide novel outstanding properties . Specifically, hydrogel coatings take advantage of hydrogels peculiar ability of releasing in a controlled space–time manner to the therapeutic target the entrapped bioactive agents (drugs, proteins, peptides, growth factors, inorganic or polymeric nanoparticles, and nucleic acids) through their polymeric network .
Bioactive agents controlled delivery reduces side effects in patients undergoing implant procedures. In addition, highly stable (from hours to months) hydrogel coatings with great loading ability provide a not sudden, uniform, and prolonged release of specific low- to high-doses . This way, therapeutic effect of bioactive substances is extended, and the over-excessed concentration peaks of conventional methods are diminished. These features endow hydrogel coatings with privileged pharmacokinetic profiles, which can be modulated for personalized therapies . Further, hydrogel coatings do not need to modulate specific linkages to release bioactive agents since their release mechanisms are mainly governed by simple diffusion, swelling, and degradation processes .
Nowadays, researchers are focusing their attention is the hinder of hydrogel coatings attachment to surfaces, which occurs due to hydrogels excessively huge swelling and macroscale thickness. One promising alternative approach to create highly adhesive hydrogel coatings with strong and resistant hydrogel-surface attachment is the
The number of works related to the development of novel biopolymer-based hydrogel systems, mainly those synthesized with hyaluronic acid and chitosan, that promote the sustained release of bioactive agents increases year by year. In the current chapter we have summarized the recent accomplishments of biopolymer based physical and chemically crosslinked hydrogels, as well as hydrogel coatings for drug delivery and sustained release applications. The future perspectives in this field involve the development of hydrogel based medicines with specific temporal and spatial controlled release of drugs. Such medicines afford dose control, local delivery and reduced side effects that increase the efficacy and security of the treatment and the adherence of the patient to it. This strategy will lower pharmaceutical costs and improve the quality of life of the patient and the society overall.
Jon Andrade del Olmo thanks Basque Government for “Program of Industrial Doctorates. Bikaintek 2018” (exp number 01-AF-W2-2018-00002).
Conflict of interest
All the authors are employees of the company i+Med S. Coop.
Alonso JM, Andrade del Olmo J, Perez Gonzalez R, Saez-Martinez V. Injectable hydrogels: From laboratory to industrialization. Polymers. 2021 Feb 22; 13:650. DOI: 10.3390/polym13040650
Muir VG, Burdick JA. Chemically modified biopolymers for the formation of biomedical hydrogels. Chemical Reviews. 2021; 121:10908-10949. DOI: 10.1021/acs.chemrev.0c00923
Guvendiren M, Lu HD, Burdick JA. Shear-thinning hydrogels for biomedical applications. Soft Matter. 2012; 8:260-272. DOI: 10.1039/c1sm06513k
Bahram M, Mohseni N, Moghtader M. An introduction to hydrogels and some recent applications. In: Majee SB, editor. Emerging Concepts in Analysis and Applications of Hydrogels. London: Intechopen; 2016. pp. 9-38. DOI: 10.5772/64301
Pérez LA, Hernández R, Alonso JM, Pérez-González R, Sáez-Martínez V. Hyaluronic acid hydrogels crosslinked in physiological conditions: Synthesis and biomedical applications. Biomedicine. 2021; 9:1-20. DOI: 10.3390/biomedicines9091113
de Lima CSA, Balogh TS, Varca JPRO, Varca GHC, Lugão AB, Camacho-Cruz LA, et al. An updated review of macro, micro, and nanostructured hydrogels for biomedical and pharmaceutical applications. Pharmaceutics. 2020; 12:1-28. DOI: 10.3390/pharmaceutics12100970
Mandal A, Clegg JR, Anselmo AC, Mitragotri S. Hydrogels in the clinic. Bioengineering and Translational Medicine. 2020; 5:1-12. DOI: 10.1002/btm2.10158
Rizzo F, Kehr NS. Recent advances in injectable hydrogels for controlled and local drug delivery. Advanced Healthcare Materials. 2021; 10:1-26. DOI: 10.1002/adhm.202001341
Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nature Reviews Materials. 2016; 1:16071. DOI: 10.1038/natrevmats.2016.71
Young ME, Carroad PA, Bell RL. Estimation of diffusion coefficients of proteins. Biotechnology and Bioengineering. 1980; 22(5):947-955. DOI: 10.1002/bit.260220504
Caccavo D. An overview on the mathematical modeling of hydrogels’ behavior for drug delivery systems. International Journal of Pharmaceutics. 2019; 560:175-190. DOI: 10.1016/j.ijpharm.2019.01.076
Wu L, Brazel CS. Mathematical model to predict drug release, including the early-time burst effect, from swellable homogeneous hydrogels. Industrial and Engineering Chemistry Research. 2008; 47(5):1518-1526. DOI: 10.1021/ie071139m
Sheth S, Barnard E, Hyatt B, Rathinam M, Zustiak SP. Predicting drug release from degradable hydrogels using fluorescence correlation spectroscopy and mathematical modeling. Frontiers in Bioengineering and Biotechnology. 2019; 7:1-12. DOI: 10.3389/fbioe.2019.00410
Tang S, Zhao L, Yuan J, Chen Y, Leng Y. Physical hydrogels based on natural polymers. In: Chen Y, editor. Hydrogels Based on Natural Polymers. Amsterdam: Elsevier; 2020. pp. 51-89. DOI: 10.1016/B978-0-12-816421-1.00003-3
Bustamante-Torres M, Romero-Fierro D, Arcentales-Vera B, Palomino K, Magaña H, Bucio E. Hydrogels classification according to the physical or chemical interactions and as stimuli-sensitive materials. Gels. 2021; 7:1-25. DOI: 10.3390/gels7040182
Jensen BEB, Edlund K, Zelikin AN. Micro-structured, spontaneously eroding hydrogels accelerate endothelialization through presentation of conjugated growth factors. Biomaterials. 2015; 49:113-124. DOI: 10.1016/j.biomaterials.2015.01.036
Boontheekul T, Kong HJ, Mooney DJ. Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution. Biomaterials. 2005; 26:2455-2465. DOI: 10.1016/j.biomaterials.2004.06.044
Zustiak SP, Leach JB. Characterization of protein release from hydrolytically degradable poly(ethylene glycol) hydrogels. Biotechnology and Bioengineering. 2011; 108:197-206. DOI: 10.1002/bit.22911
Chandrawati R. Enzyme-responsive polymer hydrogels for therapeutic delivery. Experimental Biology and Medicine. 2016; 241(9):972-979. DOI: 10.1177/1535370216647186
Silva EA, Mooney DJ. Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis. Journal of Thrombosis and Haemostasis. 2007; 5:590-598. DOI: 10.1111/j.1538-7836.2007.02386.x
Silva EA, Kim ES, Hyun JK, Mooney DJ. Material-based deployment enhances efficacy of endothelial progenitor cells. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105:14347-14352. DOI: 10.1073/pnas.0803873105
Kopeček J, Yang J. Peptide-directed self-assembly of hydrogels. Acta Biomaterialia. 2009; 5:805-816. DOI: 10.1016/j.actbio.2008.10.001
Lim DW, Nettles DL, Setton LA, Chikoti A. Rapid crosslinking of elastin-like polypeptides with Hydroxymethylphosphines in aqueous solution. Biomacromolecules. 2007; 8:1463-1470. DOI: 10.1021/bm061059m
Wieduwild R, Tsurkan M, Chwalek K, Murawala P, Nowak M, Freudenberg U, et al. Minimal peptide motif for non-covalent peptide-heparin hydrogels. Journal of the American Chemical Society. 2013; 135:2919-2922. DOI: 10.1021/ja312022u
Vulic K, Shoichet MS. Tunable growth factor delivery from injectable hydrogels for tissue engineering. Journal of the American Chemical Society. 2012; 134:882-885. DOI: 10.1021/ja210638x
Micklitsch CM, Knerr PJ, Branco MC, Nagarkar R, Pochan DJ, Schneider JP. Zinc-triggered hydrogelation of a self-assembling β-hairpin peptide. Angewandte Chemie, International Edition. 2011; 50:1577-1579. DOI: 10.1002/anie.201006652
Neufeld L, Bianco-Peled H. Pectin–chitosan physical hydrogels as potential drug delivery vehicles. International Journal of Biological Macromolecules. 2017; 101:852-861. DOI: 10.1016/j.ijbiomac.2017.03.167
Ishii S, Kaneko J, Nagasaki Y. Development of a long-acting, protein-loaded, redox-active, injectable gel formed by a polyion complex for local protein therapeutics. Biomaterials. 2016; 84:210-218. DOI: 10.1016/j.biomaterials.2016.01.029
Mitura S, Sionkowska A, Jaiswal A. Biopolymers for hydrogels in cosmetics: Review. Journal of Materials Science. Materials in Medicine. 2020; 31:50. DOI: 10.1007/s10856-020-06390-w
Kasiński A, Zielińska-Pisklak M, Oledzka E, Sobczak M. Smart hydrogels – Synthetic stimuli-responsive antitumor drug release systems. International Journal of Nanomedicine. 2020; 15:4541-4572. DOI: 10.2147/IJN.S248987
Ganie SA, Ali A, Mir TA, Li Q. Physical and chemical modification of biopolymers and biocomposites. In: Hamed S, editor. Advanced Green Materials. Fabrication, Characterization and Applications of Biopolymers and Biocomposites. Duxford: Woodhead Publishing; 2021. pp. 359-377. DOI: 10.1016/B978-0-12-819988-6.00016-1
Burdick JA, Prestwich GD. Hyaluronic acid hydrogels for biomedical applications. Advanced Materials. 2011; 23:41-56. DOI: 10.1002/adma.201003963
Zargar V, Asghari M, Dashti A. A review on chitin and chitosan polymers: Structure, chemistry, solubility, derivatives, and applications. ChemBioEng Reviews. 2015; 2:204-226. DOI: 10.1002/cben.201400025
Bakshi PS, Selvakumar D, Kadirvelu K, Kumar NS. Chitosan as an environment friendly biomaterial – A review on recent modifications and applications. International Journal of Biological Macromolecules. 2020; 150:1072-1083. DOI: 10.1016/j.ijbiomac.2019.10.113
Guaresti O, García–Astrain C, Palomares T, Alonso–Varona A, Eceiza A, Gabilondo N. Synthesis and characterization of a biocompatible chitosan–based hydrogel cross–linked via ‘click’ chemistry for controlled drug release. International Journal of Biological Macromolecules. 2017; 102:1-9. DOI: 10.1016/j.ijbiomac.2017.04.003
Andrade del Olmo J, Pérez-Álvarez L, Sáez-Martínez V, Benito-Cid S, Ruiz-Rubio L, Pérez-González R, et al. Wound healing and antibacterial chitosan-genipin hydrogels with controlled drug delivery for synergistic anti-inflammatory activity. International Journal of Biological Macromolecules. 2022; 203:679-694. DOI: 10.1016/j.ijbiomac.2022.01.193
Lou C, Tian X, Deng H, Wang Y, Jiang X. Dialdehyde-β-cyclodextrin-crosslinked carboxymethyl chitosan hydrogel for drug release. Carbohydrate Polymers. 2020; 231:115678. DOI: 10.1016/j.carbpol.2019.115678
Bashir S, Teo YY, Ramesh S, Ramesh K. Physico-chemical characterization of pH-sensitive N-Succinyl chitosan-g-poly (acrylamide-co-acrylic acid) hydrogels and in vitro drug release studies. Polymer Degradation and Stability. 2017; 139:38-54. DOI: 10.1016/j.polymdegradstab.2017.03.014
Wang Y, Wang J, Yuan Z, Han H, Li T, Li L, et al. Chitosan cross-linked poly(acrylic acid) hydrogels: Drug release control and mechanism. Colloids and Surfaces. B, Biointerfaces. 2017; 152:252-259. DOI: 10.1016/j.colsurfb.2017.01.008
Andrade del Olmo J, Alonso JM, Sáez Martínez V, Ruiz-Rubio L, Pérez González R, Vilas-Vilela JL, et al. Biocompatible hyaluronic acid-divinyl sulfone injectable hydrogels for sustained drug release with enhanced antibacterial properties against Staphylococcus aureus. Materials Science and Engineering: C. 2021; 125:112102. DOI: 10.1016/j.msec.2021.112102
Kim MH, Park JH, Nguyen DT, Kim S, Jeong DI, Cho HJ, et al. Hyaluronidase inhibitor-incorporated cross-linked hyaluronic acid hydrogels for subcutaneous injection. Pharmaceutics. 2021; 13:1-16. DOI: 10.3390/pharmaceutics13020170
Xu K, Yao H, Fan D, Zhou L, Wei S. Hyaluronic acid thiol modified injectable hydrogel: Synthesis, characterization, drug release, cellular drug uptake and anticancer activity. Carbohydrate Polymers. 2021; 254:117286. DOI: 10.1016/j.carbpol.2020.117286
Zhang Y, Li X, Zhong N, Huang Y, He K, Ye X. Injectable in situ dual-crosslinking hyaluronic acid and sodium alginate based hydrogels for drug release. Journal of Biomaterials Science. Polymer Edition. 2019; 30:995-1007. DOI: 10.1080/09205063.2019.1618546
Xu X, Zeng Z, Huang Z, Sun Y, Huang Y, Chen J, et al. Near-infrared light-triggered degradable hyaluronic acid hydrogel for on-demand drug release and combined chemo-photodynamic therapy. Carbohydrate Polymers. 2020; 229:115394. DOI: 10.1016/j.carbpol.2019.115394
Ziadlou R, Rotman S, Teuschl A, Salzer E, Barbero A, Martin I, et al. Optimization of hyaluronic acid-tyramine/silk-fibroin composite hydrogels for cartilage tissue engineering and delivery of anti-inflammatory and anabolic drugs. Materials Science and Engineering: C. 2021; 120:111701. DOI: 10.1016/j.msec.2020.111701
Hwang CR, Lee SY, Kim HJ, Lee KJ, Lee J, Kim DD, et al. Polypseudorotaxane and polydopamine linkage-based hyaluronic acid hydrogel network with a single syringe injection for sustained drug delivery. Carbohydrate Polymers. 2021; 266:118104. DOI: 10.1016/j.carbpol.2021.118104
Mousavi Nejad Z, Torabinejad B, Davachi SM, Zamanian A, Saeedi Garakani S, Najafi F, et al. Synthesis, physicochemical, rheological and in-vitro characterization of double-crosslinked hyaluronic acid hydrogels containing dexamethasone and PLGA/dexamethasone nanoparticles as hybrid systems for specific medical applications. International Journal of Biological Macromolecules. 2019; 126:193-208. DOI: 10.1016/j.ijbiomac.2018.12.181
Hu B, Gao M, Boakye-Yiadom KO, Ho W, Yu W, Xu X, et al. An intrinsically bioactive hydrogel with on-demand drug release behaviors for diabetic wound healing. Bioactive Materials. 2021; 6:4592-4606. DOI: 10.1016/j.bioactmat.2021.04.040
Qiao Y, Xu S, Zhu T, Tang N, Bai X, Zheng C. Preparation of printable double-network hydrogels with rapid self-healing and high elasticity based on hyaluronic acid for controlled drug release. Polymer. 2020; 186:121994. DOI: 10.1016/j.polymer.2019.121994
Culebras M, Pishnamazi M, Walker GM, Collins MN. Facile tailoring of structures for controlled release of paracetamol from sustainable lignin derived platforms. Molecules. 2021; 26:1-9. DOI: 10.3390/molecules26061593
Culebras M, Barrett A, Pishnamazi M, Walker GM, Collins MN. Wood-derived hydrogels as a platform for drug-release systems. ACS Sustainable Chemistry & Engineering. 2021; 9:2515-2522. DOI: 10.1021/acssuschemeng.0c08022
Davidson-Rozenfeld G, Stricker L, Simke J, Fadeev M, Vázquez-González M, Ravoo BJ, et al. Light-responsive arylazopyrazole-based hydrogels: Their applications as shape-memory materials, self-healing matrices and controlled drug release systems. Polymer Chemistry. 2019; 10:4106-4115. DOI: 10.1039/c9py00559e
Verhoeven E, Vervaet C, Remon JP. Xanthan gum to tailor drug release of sustained-release ethylcellulose mini-matrices prepared via hot-melt extrusion: in vitro and in vivo evaluation. European Journal of Pharmaceutics and Biopharmaceutics. 2006; 63:320-330. DOI: 10.1016/j.ejpb.2005.12.004
Sharma PK, Taneja S, Singh Y. Hydrazone-linkage-based self-healing and injectable xanthan-poly (ethylene glycol) hydrogels for controlled drug release and 3D cell culture. ACS Applied Materials & Interfaces. 2018; 10:30936-30945. DOI: 10.1021/acsami.8b07310
Suflet DM, Popescu I, Prisacaru AI, Pelin IM. Synthesis and characterization of curdlan–phosphorylated curdlan based hydrogels for drug release. International Journal of Polymeric Materials and Polymeric Biomaterials. 2021; 70:870-879. DOI: 10.1080/00914037.2020.1765360
Wang X, Gou C, Gao C, Song Y, Zhang J, Huang J, et al. Synthesis of casein-γ-polyglutamic acid hydrogels by microbial transglutaminase-mediated gelation for controlled release of drugs. Journal of Biomaterials Applications. 2021; 36:237-245. DOI: 10.1177/08853282211011724
Zhang L, Chen L. A review on biomedical titanium alloys: Recent progress and prospect. Advanced Engineering Materials. 2019; 21:1801215. DOI: 10.1002/adem.201801215
Bahl S, Suwas S, Chatterjee K. Comprehensive review on alloy design, processing, and performance of β titanium alloys as biomedical materials. International Materials Review. 2021; 66:114-139. DOI: 10.1080/09506608.2020.1735829
Marques A, Miranda G, Silva F, Pinto P, Carvalho Ó. Review on current limits and potentialities of technologies for biomedical ceramic scaffolds production. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2021; 109:377-393. DOI: 10.1002/jbm.b.34706
Rebelo R, Fernandes M, Fangueiro R. Biopolymers in medical implants: A brief review. Procedia Engineering. 2017; 200:236-243. DOI: 10.1016/j.proeng.2017.07.034
Alizadeh-Osgouei M, Li Y, Wen C. A comprehensive review of biodegradable synthetic polymer-ceramic composites and their manufacture for biomedical applications. Bioactive Materials. 2019; 4:22-36. DOI: 10.1016/j.bioactmat.2018.11.003
Jiao J, Zhang S, Qu X, Yue B. Recent advances in research on antibacterial metals and alloys as implant materials. Frontiers in Cellular and Infection Microbiology. 2021; 11:1-19. DOI: 10.3389/fcimb.2021.693939
Kurup A, Dhatrak P, Khasnis N. Surface modification techniques of titanium and titanium alloys for biomedical dental applications: A review. Materials Today: Proceedings. 2020; 39:84-90. DOI: 10.1016/j.matpr.2020.06.163
Nour S, Baheiraei N, Imani R, Rabiee N, Khodaei M, Alizadeh A, et al. Bioactive materials: A comprehensive review on interactions with biological microenvironment based on the immune response. Journal of Bionic Engineering. 2019; 16:563-581. DOI: 10.1007/s42235-019-0046-z
Rau JV, Antoniac I, Cama G, Komlev VS, Ravaglioli A. Bioactive materials for bone tissue engineering. BioMed Research International. 2016; 2016:1-3. DOI: 10.1155/2016/3741428
Ibrahim MZ, Sarhan AAD, Yusuf F, Hamdi M. Biomedical materials and techniques to improve the tribological, mechanical and biomedical properties of orthopedic implants – A review article. Journal of Alloys and Compounds. 2017; 714:636-667. DOI: 10.1016/j.jallcom.2017.04.231
Priyadarshini B, Rama M, Chetan VU. Bioactive coating as a surface modification technique for biocompatible metallic implants: A review. Journal of Asian Ceramic Societies. 2019; 7:397-406. DOI: 10.1080/21870764.2019.1669861
Olmo JA-D, Ruiz-Rubio L, Pérez-Alvarez L, Sáez-Martínez V, Vilas-Vilela JL. Antibacterial coatings for improving the performance of biomaterials. Coatings. 2020; 10:139. DOI: 10.3390/coatings10020139
Tan G, Xu J, Chirume WM, Zhang J, Zhang H, Hu X. Antibacterial and anti-inflammatory coating materials for Orthopedic implants: A review. Coatings. 2021 Nov; 11:1401. DOI: 10.3390/coatings11111401
Xiong P, Yan JL, Wang P, Jia ZJ, Zhou W, Yuan W, et al. A pH-sensitive self-healing coating for biodegradable magnesium implants. Acta Biomaterialia. 2019; 98:160-173. DOI: 10.1016/j.actbio.2019.04.045
Wang X, Chang J, Wu C. Bioactive inorganic/organic nanocomposites for wound healing. Applied Materials Today. 2018; 11:308-319. DOI: 10.1016/j.apmt.2018.03.001
Hu C, Ashok D, Nisbet DR, Gautam V. Bioinspired surface modification of orthopedic implants for bone tissue engineering. Biomaterials. 2019; 219:119366. DOI: 10.1016/j.biomaterials.2019.119366
Zafar MS, Farooq I, Awais M, Najeeb S, Khurshid Z, Zohaib S. Bioactive surface coatings for enhancing osseointegration of dental implants. In: Kaur G, editor. Biomedical, Therapeutic and Clinical Applications of Bioactive Glasses. Duxford: Woodhead Publishing; 2018. pp. 313-329. DOI: 10.1016/B978-0-08-102196-5.00011-2
del Olmo JA, Pérez-Álvarez L, Pacha-Olivenza MÁ, Ruiz-Rubio L, Gartziandia O, Vilas-Vilela JL, et al. Antibacterial catechol-based hyaluronic acid, chitosan and poly (N-vinyl pyrrolidone) coatings onto Ti6Al4V surfaces for application as biomedical implant. International Journal of Biological Macromolecules. 2021; 183:1222-1235. DOI: 10.1016/j.ijbiomac.2021.05.034
Zhao C, Zhou L, Chiao M, Yang W. Antibacterial hydrogel coating: Strategies in surface chemistry. Advances in Colloid and Interface Science. 2020; 285:102280. DOI: 10.1016/j.cis.2020.102280
Sáez V, Hernáez E, López L. Liberación controlada de fármacos. Aplicaciones biomédicas. Revista iberoamericana de polímeros. 2003; 4(2):111-122
Liu J, Qu S, Suo Z, Yang W. Functional hydrogel coatings. National Science Review. 2021; 8:nwaa254. DOI: 10.1093/nsr/nwaa254/5918005
Sánchez-Bodón J, Del Olmo JA, Alonso JM, Moreno-Benítez I, Vilas-Vilela JL, Pérez-Álvarez L. Bioactive coatings on titanium: A review on hydroxylation, self-assembled monolayers (SAMs) and surface modification strategies. Polymers. 2022; 14:165. DOI: 10.3390/polym14010165
Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. International Journal of Pharmaceutics. 1983; 15(1):25-35. DOI: 10.1016/0378-5173(83)90064-9
Li W, Liu X, Deng Z, Chen Y, Yu Q , Tang W, et al. Tough bonding, on-demand debonding, and facile rebonding between hydrogels and diverse metal surfaces. Advanced Materials. 2019; 31:1904732. DOI: 10.1002/adma.201904732