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Review Article
 

Biomaterials-based Hydrogels and their Drug Delivery Potentialities



Angel M. Villalba-Rodriguez, Kuldeep Dhama and Hafiz M.N. Iqbal
 
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ABSTRACT

In recent years, biomaterials-based hydrogels have gained special attention and moved into mainstream applications in various biomedical sectors. The pristine or improved characteristics of biomaterials-based hydrogels offer unique dimensions in changing the dynamics of 21st-century drug delivery applications. In this context, numerous researchers and research-based organizations have reported uniqueness and novel aspects of various biomaterials for drug delivery purposes and different approaches including in vitro, in vivo and ex-vivo techniques have been exploited, so far. Among various potent biomaterials, chitosan, poly(lactic-co-glycolic acid) (PLGA) and bacterial cellulose are of supreme interests due to their tunable multi-functionalities for an enhanced and efficient delivery. In addition, several characteristics including unique chemical structure, bioactivity, non-toxicity, biocompatibility, biodegradability, recyclability, etc. all positioned them well in various biomedical, pharmaceutical and nutraceutical sectors of the modern world. Herein, we reviewed biomaterials (chitosan, poly(lactic-co-glycolic acid) (PLGA) and bacterial cellulose) based hydrogels and their drug delivery potentialities. The information is also given on considerable future directions that can help in addressing the left behind research gaps and outstanding questions in future studies.

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Angel M. Villalba-Rodriguez, Kuldeep Dhama and Hafiz M.N. Iqbal, 2017. Biomaterials-based Hydrogels and their Drug Delivery Potentialities. International Journal of Pharmacology, 13: 864-873.

DOI: 10.3923/ijp.2017.864.873

URL: https://scialert.net/abstract/?doi=ijp.2017.864.873

INTRODUCTION

In the past few decades, the use of biomaterials has grown exponentially due to the ease to acquire these materials and the low costs required to do so but most importantly because of the huge amount of biomedical and biotechnological applications in which they can be used. Whether it be materials obtained from natural sources such as living organisms, or materials used in applications where they must interact with biological systems even though they are synthetic materials with enough biocompatibility. Biomaterials are natural candidates for the aforementioned fields of research and engineering. Many bio-based materials including chitin, chitosan, bacterial cellulose, alginate and keratin, among others have been fully characterized and well organized/developed into value-added structures1-13. Thus, provide a proper route to emulate bio-systems-a biomimetic approach to eliminate the concerns like unfavorable immune responses, disease transmission, effective wound healing, control delivery and regeneration potentialities11. The main objective of these materials is to enhance the quality of life in a sustainable manner by avoiding the exploitation of synthetic materials from sources such as petroleum13.

A type of biomaterial extensively used for biomedical, medical and biotechnological applications are hydrogels. Hydrogels are water-swollen polymeric materials that maintain a three-dimensional structure and they are in fact the first biomaterial purposely designed for human use in the early 1950s while researchers were working in the design of new biomaterials for ophthalmology14. Due to their high moisture content, biomaterials in the form of hydrogels are often used as artificial skin materials, contact lenses, cardiovascular tissue engineering, biosensor membranes and drug delivery systems15-19.

Hydrogels can be classified from the perspective of their source: Natural or synthetic hydrogels; the nature of their network: homopolymer networks, copolymer networks, interpenetrating networks, or double networks; their degree of porosity: Homogeneous (transparent) hydrogels, microporous and macroporous hydrogels, which can be controlled by their cross-linking nature and aids in the uploading of the drugs and their degradability: Degradable or non-degradable hydrogels. Hydrogels, especially those from natural sources, are biocompatible biomaterials due to their high water content within their porous structures, their chemical structure, biological activity, low toxicity and biodegradability19.

Bulk and surface properties of a hydrogel such as mechanical properties, thermal properties, chemical structure, durability, biocompatibility and functionality are highly considered for biomedical applications. These are among a few examples of the most important properties to take into account while defining which materials, methods, treatments and procedures will be used for accomplishing a certain requirement. One important property found in hydrogels is their hydrophilicity. This capacity of a material to interact with water not only without rejecting it but keeping it inside its structure, makes hydrogels especially important in applications in which the biological system needs to be kept hydrated, such as contact lenses20.

Among the ever-increasing amount polymeric materials used for the development of hydrogels for applications such as drug delivery systems and tissue engineering regarding the biomedical field, we can find a wide range of polymers from natural sources. Some of the biopolymers and their composites recently studied by researchers in this field are chitosan, sodium alginate, bacterial cellulose, polyvinyl alcohol (PLA), poly(lactic-co-glycolic acid) (PLGA) and its copolymers21-24.

Herein, an effort has been made to highlight the unique potentialities of biomaterials including chitosan, poly(lactic-co-glycolic acid) (PLGA) and bacterial cellulose. A noticeable progress has already been made in the modification of natural biomaterials though using various routes including chemical, physical, physiochemical, or biological based approaches to modify/impart broader applications that individual materials fail to demonstrate on their own. A special focus has been given to drug delivery potentialities. The first part of the review discusses the chitosan-based hydrogels as novel drug delivery vehicles. In the second part, the focus has been given to PLGA-based hydrogels with drug delivery perspectives. The third part comprised of the bacterial cellulose-based hydrogels for drug delivery applications. Finally, last part of the work is focused on considerable future directions that can help in addressing the left behind research gaps and outstanding questions in future studies.

Chitosan-based hydrogels in drug delivery systems: Chitosan is a polysaccharide that can be produced at low costs from the deacetylation of chitin found in the exoskeletons of shrimp, crab, prawn and other crustaceans, as well as some insects. Its abundance in such natural sources, biocompatibility, biodegradability, non-toxicity, antiviral and antibacterial properties allow this biomaterial and its combinations with other materials to be an excellent candidate for biomedical applications such as drug delivery systems. Additionally, it has outstanding potential to participate as an outstanding polymeric matrix for drug-loaded hydrogels19. Figure 1 illustrates a schematic representation of drug-loaded chitosan-based hydrogel development in the presence of a cross-linking agent.

Image for - Biomaterials-based Hydrogels and their Drug Delivery Potentialities
Fig. 1: Development of drug-loaded chitosan-based hydrogel in the presence of the cross-linking agent

There are many routes of administration for drug delivery systems depending on the area reached or the pathogen being treated. Routes of administration for drug delivery systems are classified into three groups, topical, enteral and parenteral. This depends whether the effect is local (in topical administration) or systemic (in enteral and parenteral administration routes). Examples of topical routes of administration are nasal, otic (ear drops), ophthalmic and epicutaneous. Enteral routes involve any part of the gastrointestinal tract such as oral and rectal routes. Lastly, parenteral routes are those who do not involve the gastrointestinal tract, such as intravenous, intra-arterial, intramuscular, intracerebral and subcutaneous routes25-28.

Chitosan hydrogels for drug delivery systems have been reported for several routes of administration. In recent reports related to topical route of drug delivery systems, various research groups have approached the nasal application of hydrogels of chitosan-based composites. A thermosensitive hydrogel of quaternized chitosan and poly(ethylene glycol) (PEG) was developed by Wu et al.29 for the nasal route of administration of insulin and the in vitro tests of the drug release behavior showed that the initial release of the drug was very quick but its release rate slowed down after several hours. This indicated that a fraction of the drug was adsorbed on the surface of the hydrogel or distributed in the interstitial spaces within the structure of the hydrogel. Afterward, the insulin within the hydrogel was slowly released due to the hydrogel swelling and its bulk erosion. Hydrogel erosion can be measured by its weight loss as a function of time30.

Regarding injectable chitosan-based hydrogels, there have been reports on injectable, thermoreversible chitosan-based hydrogels for sustained release of proteins. In this study, they had a chitosan-PEG (polyethylene glycol) copolymer made by chemically grafting mono hydroxy PEG onto the chitosan polymeric backbone. It was observed that by optimizing the copolymer’s PEG content, it gained a thermoreversible transition between an injectable solution at room temperature and a hydrogel at body temperature31,32. In this context, Peng et al.33 developed injectable and biodegradable, thermosensitive chitosan-based hydrogels loaded with PHBHHx (poly(3-hydroxybutyrate-co-3hydroxyhexanoate)) nanoparticles for the long-term sustained release of insulin phospholipid complex. In this study, in vitro tests showed that only 19.11% of the insulin was released from the nanoparticle-loaded hydrogel in 31 days. While in another sample without nanoparticles but only free insulin-loaded into the hydrogel, 96.41% of the total insulin was released in only 16 days. This showed how nanoparticles have a considerable impact on the duration of the insulin release and how they can affect to make it more sustainable and controlled for customization in terms of the timing needed in the application.

Researchers have tried different approaches on the drug loading capability of chitosan-based hydrogels by exploring different network architectures of the hydrogels. This change in the morphology through the application of different cross-linkers changes the bulk structure of the hydrogels, thus having an impact on their drug-loading capacity24. Other groups have studied other aspects regarding the importance of structural and viscoelastic properties of chitosan-based hydrogels in drug delivery applications. In this context, chitosan-based biocomposites are combinations of chitosan blended or mixed with other polymers, fibers or particles, to have a modification in its properties based on the application. Islam et al.34 observed the structural and viscoelastic behavior, cell cytotoxicity and progesterone release of silane cross-linked chitosan/poly(vinyl alcohol) (PVA) hydrogels. In this study, they observed the presence of siloxane linkage, as well as inter- and intramolecular hydrogen bonding between the polymeric chains. The viscoelastic behavior of the material in terms of storage and loss moduli (G’ and G", respectively) decreased as temperature and cross-linking density increased. It was also observed that the stability of the gel structure was directly proportional to the increase of storage modulus (G’).

Image for - Biomaterials-based Hydrogels and their Drug Delivery Potentialities
Fig. 2: Bio-responsive behavior of control drug release subject to pH and temperature change

In the case of cytotoxicity studies, they confirmed that chitosan/PVA hydrogels are non-toxic to fibroblast cells and have a switchable pH-response behavior, which has been exploited for the controlled release of progesterone in gastrointestinal track34,35. The bio-responsive behavior of control drug release subject to pH and temperature change is shown in Fig. 2.

Plga-based hydrogels in drug delivery systems: Poly(lactic-co-glycolic acid) (PLGA) is a biocompatible, biodegradable copolymer synthesized by the ring-opening copolymerization of glycolic acid and lactic acid. The PLGA has been successfully proved as a biodegradable material since it undergoes hydrolysis in the body to produce its original monomers36. The PLGA has also been used extensively in the form of nanoparticles as a reservoir for the encapsulation of many therapeutic active compounds such as paclitaxel, docetaxel, thymopentin, dexamethasone and taxol37-41. This confirms PLGA as a viable biomaterial for drug delivery applications not only in the form of nanoparticles but also in morphologies such as nanofibers, microspheres, tablets, thin films and hydrogels42,43.

The PLGA-PEG-PLGA triblock copolymer hydrogels with thermosensitive properties for the treatment of osteosarcoma, loaded with PLK1shRNA and doxorubicin were developed and characterized by Ma et al.44. They reported that the hydrogels loaded with both active compounds had better antitumor efficacy than having one or the other alone injected into mice with osteosarcoma. Said combination of drugs accomplished almost complete suppression of tumor growth up to 16 days. There have also been other studies regarding the drug-loading of PLGA-based copolymer hydrogels with doxorubicin for treating cancerous tumors. One property relevant to in-vivo studies of hydrogels is their thermogelling properties due to their behavior at varying temperatures and their reversible sol-gel transition. This thermogelling behavior was observed not to be affected by the addition of doxorubicin, having the composite behave as a solution at room temperature (25°C) and become a gel at physiological temperature (37°C), examined through rheological studies. It was observed that the controlled release of the drug has more efficacy in the treatment of tumors than injecting the drug on its own45.

In contrast to the previously mentioned triblock copolymers (PLGA-PEG-PLGA), other combinations of these triblock can be developed by using the same ring-opening polymerization method but varying the order of the polymers within the polymeric chain or the materials used, such as a triblock copolymer made up of PEG-PLGA-PEG. Hydrogels consisting of these copolymers have displayed both higher and lower critical solution temperatures, as well as being processable without the need of high temperature to dissolve the polymers. Hydrogels made with PEG-PLGA-PEG copolymers showed that their sol-gel transition was directly proportional to the molecular weights of PEG and PLGA and the ratio of lactic acid to glycolic acid in their structure. Hydrogels with pH and temperature responses have shown to have some advantages over those that are only responsive to temperature, such as to prevent gelation within the injection needle or route, as well as to form better ionic complexes with pharmaceutical compounds46.

Regarding the gelation properties of hydrogels, rheological studies are a key factor. Since thermosensitive hydrogels respond to environmental temperature conditions, these changes also affect their rheological properties and, therefore, their sol-gel states. These viscoelastic and mechanical properties are valuable for in-situ drug delivery applications, due to their impact on the injectability and drug release of the hydrogels47. Another field of research being currently explored is that of PLGA-based triblock copolymers for the delivery of osteogenesis drugs in bone tissue regeneration for patients with bone defects. The PLGA-PEG-PLGA hydrogels loaded with simvastatin for cell differentiation and mineralization, for an improved regeneration of bone were developed and it was found that the drug did not affect cell proliferation and its effect on bone formation was observed through in vitro and in vivo experiments, showing that the drug-loaded hydrogel has potential clinical applications in bone defect regeneration47.

The massive array of PLGA-based triblock copolymer hydrogels for drug delivery wound healing and tissue regeneration applications are widely studied by experts of the field, aiming towards the full comprehension and understanding of these materials as a bio-friendly alternative in terms of materials engineering. Applications such as implantable devices for sensing systems have also demonstrated significant potential. These devices can be implanted through minimally invasive procedures, although they present challenges such as the host not fully accepting the implant or foreign body reactions of the host towards the implant. However, micro- and nano-technology contribute for the modification of the design and properties of these implantable devices in order to obtain better outcomes against the aforementioned clinical challenges.

Bacterial cellulose hydrogels in drug delivery systems: Bacterial cellulose is a polysaccharide secreted by bacteria in the form of long nanofibrils. This extracellular cellulose has been proven to have high mechanical strength, thermal stability, high water content, high crystallinity and a highly pure laminated nanofiber structure. The reason why this material has a high tensile modulus in the direction of the nanofiber layers when compared to other biomaterials is that of its anisotropic mechanical behavior, caused by its laminated structure. Bacterial cellulose has been recently under research as a biotechnological approach for the synthesis of novel constructs for drug-delivery applications (Table 1). Due to the wide variety of applications of plant-based cellulose such as tissue engineering, drug delivery systems and biosensors, bacterial cellulose is a promising biomaterial since it presents higher mechanical properties than higher plant cellulose, while also giving investigators to produce, as well a synthesize it in their laboratories. This makes bacterial cellulose a greener approach for the synthesis of biomaterials57. Drug delivery and other biomedical applications of bacterial cellulose as a promising biomaterial are shown in Fig. 358.

From the perspective of mechanical properties, bacterial cellulose has been compared with porcine carotid arteries and expanded polytetrafluoroethylene. This was tested to present information on the viability of bacterial cellulose as a possible candidate biomaterial for tissue engineered blood vessels, due to its biocompatibility, non-toxicity and excellent mechanical properties. Mechanically, bacterial cellulose presents a more similar behavior to porcine carotid arteries than to expanded polytetrafluoroethylene, most likely due to the similarity in the nanofiber network structure of both materials. However, porcine carotid arteries have higher stress, strain and Young’s modulus at break than bacterial cellulose. Also, smooth muscle cells showed excellent adhesion and proliferation on the bacterial cellulose sample, which is a promising behavior for the aforementioned application59,60.

While studying the properties of the material, researchers tend to put the material in different environments or conditions to observe the variation in how the material behaves under different circumstances. The mechanical properties of a material vary depending on whether the material is static or in movement. In this aspect, rheological properties of biomaterials are also important to consider, depending on the application. Rheological properties, dependent on time, have been studied for bacterial cellulose hydrogels. Strain-time curves were tested for the bacterial cellulose hydrogels at various stress levels, from 50-80% of the ultimate strength of the material. The material showed a shear modulus that changes linearly with the level of creep stress, which explains a mechanism of stiffening caused by the reorientation of the structural fibers under axial stretching61.

Based on studies done to measure the mechanical, rheological, biocompatibility and other properties of this biomaterial, bacterial cellulose has been applied for research and tests in fully functional morphologies such as tissue engineered blood vessels, ear cartilage implants and scaffolds for tissue regeneration62-64.

Table 1:Bacterial cellulose based hydrogels as drug vehicles
Image for - Biomaterials-based Hydrogels and their Drug Delivery Potentialities

Image for - Biomaterials-based Hydrogels and their Drug Delivery Potentialities
Fig. 3:
Drug delivery and other biomedical applications of bacterial cellulose (Reproduced from Ref.58, Published under CC BY-NC-SA 3.0)

Seeing how well bacterial cellulose behaves on the biomedical field due to its excellent mechanical properties and biocompatibility, it also has opened up opportunities for more interest in the drug delivery line of investigation65. Bacterial cellulose has been used as a drug delivery system, loaded with proteins and tested in vitro for measurements such as drug stability and release kinetics. The protein loaded was bovine serum albumin due to its high solubility in water, stability, abundance and acceptance as a model protein. Diffusion and swelling mechanisms did the main kinetics observed for loading and release of the protein. When compared to freeze-dried samples, the drug loading capacity was found to be higher in never-dried samples of bacterial cellulose, which could be attributed to the structural differences, making this biopolymer a competent candidate for drug delivery systems66.

Bacterial cellulose has also been combined with other materials in order to obtain bacterial cellulose-based composites in order to improve the properties of the resulting material. Ciechanska67 developed a bacterial cellulose wound healing hydrogel modified with chitosan, thus making it into a biocomposite. The resulting composite material showed excellent mechanical properties in the wet state, high moisture-keeping properties, release mechanisms of mono and oligosaccharides under lysozyme degradation which stimulates angiogenesis and tissue regeneration and antibacterial activity. Although this study was focused on wound healing, the shown enzymatic degradation of chitosan could be a potential approach for a drug release mechanism in a bacterial cellulose-chitosan composite hydrogel drug delivery system.

As it has been previously mentioned, the passive role of pharmaceutical excipients in drug delivery systems as pharmaceutical products provide important factors to consider such as weight, volume, the capacity to flow and consistency. This focus has been rapidly evolving towards more active roles for the enhancement of targeted drug delivery systems at the site of action in order to protect the drug from degradation inside the body before reaching its goal68. The synthesis of novel hydrogels for drug delivery using bacterial cellulose in combination with other materials has also been explored from the perspective of thermal and pH-based responses as mechanisms for the liberation of the pharmaceutical compounds. Acrylic acid has been used in order to complement the properties and composition of bacterial cellulose hydrogels as a thermal- and pH-responsive biocomposite excipient. The porosity of the hydrogel was determined by the concentration of acrylic acid and by the irradiation of accelerated electron beams48.

Although the crystallinity of bacterial cellulose has been shown to be relatively high when compared to other biopolymers due to its structure, it has been observed to decrease by using acrylamide grafting through cross-linking under microwave irradiation for the development of superabsorbent hydrogels with smart-swelling properties. The hydrogels were synthesized in a NaOH/urea aqueous system by using methylene bisacrylamide as the cross-linker under irradiation with microwave energy. Microwave irradiation used for the synthesis of materials has advantages over the conventional heating method such as water bath since hydrogels synthesized using microwave irradiation have greater porosity and degree of grafting. This approach also improves the degree of grafting and reduces time in the process. It also has a low energy demand and low production cost55,69,70.

Major limitations: Despite the development of various hydrogels types that could serve as important therapeutics, very few candidates have shown clinical success with a profound market value. Also, hydrogels made up of different materials have several limitations that hinder their way to the clinical success. Some of the example limitations include (1) Lower tensile strength, (2) Drug concentrations and homogeneity of loading into hydrogels (this particularly limits its application in the case of hydrophobic drugs), (3) High water uptake value and large pore sizes (this particularly limits the slow release behavior), etc. The limitations mentioned above significantly restrict the practical implementation of materials-based hydrogels as drug delivery vehicles.

Concluding remarks and future perspectives: In conclusion, various biomaterials-based hydrogels that have been identified are quickly expanding in the biomedical sector. Herein, we reviewed biomaterials (chitosan, poly(lactic-co-glycolic acid) (PLGA) and bacterial cellulose) based hydrogels and their drug delivery potentialities. Evidently, many researchers have proved that hydrogel made up of biomaterials including those have been discussed above are capable of delivering drug efficiently at the target site. However, it is important to understand the mechanisms responsible for this efficient delivery behavior. In-depth future studies are needed to unveil the role that surface functionalities of materials play in developing hydrogels with unique characteristics for efficient drug delivery applications. In this context, the ever increasing scientific knowledge and current technological advancement in biological methods could be useful for the fabrication next generation biomaterials-based hydrogels. In summary, biomaterials-based hydrogels with rational design, materials unique chemistry, remarkable in vitro, in vivo and ex vivo evaluation techniques, target specific, selectivity and efficacy would be a subject of intensive research activities in the foreseeable future.

Research gaps and outstanding questions: Despite the huge research and plethora of reported literature on the biomaterials-based hydrogels with unique characteristics, there are still outstanding issues posing questions mark and needs to address. Throughout the exploitation of various biomaterials type in their individual or mixed form, several issues have been raised on different platforms and some of them are summarized below:

Is it a cost-effective process to develop gels using multi-materials co-supported with other therapeutic agents?
What could justify the development of specific hydrogels for single use purposes?
Is it necessary to engineer new types of non-specific hydrogels which could be more useful for broader applications?
What is the maximum alkyl chain length for the generation of a bactericidal efficacy at an optimal level?
How can a robust methodology be designed to standardize the information and satisfy regulatory concerns?
What are the long-term consequences of the increased use of natural materials including those mentioned above?

SGNIFICANCE STATEMENTS

In recent years, biomaterials-based hydrogels have shown intrinsic functionalities as new vehicles for targeted drug delivery applications. With the latest developments in the materials science, the biomaterials-based hydrogels offer significant latitude in tuning unique characteristics i.e., facile synthesis, processability, thermal, mechanical and rheological behavior along with switchable features and sensitivity towards internal/external stimuli. In addition, the uniqueness of hydrogels offers a strong synergistic effect with a simultaneous co-delivery approach. This co-delivery approach significantly enhances the potency of the carrier and the therapeutic agent and together, they can reduce the incidences of drug resistance.

ACKNOWLEDGMENTS

This work was supported by the Emerging Technologies Research Group of Tec de Monterrey, Mexico. The authors (Angel M. Villalba Rodrí>guez and Hafiz M. N. Iqbal) would like to thank Tec de Monterrey, Mexico for providing literature facilities. The author (Kuldeep Dhama) thankfully acknowledge the literature facilities provided by ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India.

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