Hydrogels and Their Role in Bone Tissue Engineering: An Overview.

An increasing incidence of the bone damage either due to trauma or a wide range of diseases related to bone necessitates the advent of new technologies or modification of the existing pattern of treatment to deliver utmost care to an individual thereby helping them to lead a normal and healthy life. Revolutionary changes in the field of tissue engineering (TE) pave a way from repair to regeneration of human tissues and restoring the health of an individual. Among the numerous biomaterials available, hydrogel emerges as a promising source of scaffold material in the field of bone TE (BTE). This article presents an overview on hydrogels and their role in BTE. Copyright:

INTRODUCTION

The loss of human lives because of tissue damage and injuries to the tissues accounts for more than a million worldwide each year, which imparts a significant burden both in the aspects of the quality of life and associated health issues.[1] Despite the lack of a procedure that can present with a problem-free treatment modality, every year more than two million bone transplant procedures are being carried out worldwide.[2] Traditional surgical procedures from the aspect of bone diseases include surgical intervention, placing allograft, substituting with autograft, synthetic bone substitutes, which also present with disadvantages such as secondary infection, cost of the procedure, and demanding additional surgery.[3]

Tissue engineering (TE) aspect in healthcare has created a revolution in the way of diagnosing, planning, and implementing the treatment for a wide range of diseases from head to toe and in understanding the course and progression of the disease, thereby helping in providing a positive outcome which improves the lifestyle of an individual.[4] TE is a rapidly growing interdisciplinary field applying both the principles of bioengineering and biological sciences, which helps in fabrication of three-dimensional substitutes with close resemblance to the human tissues thereby imparting and improving, restoring, and maintaining the structural as well as functional integrity. This aspect of functional tissue fabrication in TE aids to overcome the obstacle of organ donor shortage.[5] The integration of TE techniques with orthopedic, craniofacial defects has evolved into a modern strategy such as bone TE (BTE). BTE includes vital elements such as cells, scaffolds, growth factors, and bioreactors, which are bioengineered for the desired output.[6] Scaffolds in BTE play a pivotal role in creating a bioengineered structure similar to that of the native bone in terms of quality, behavior, and internal architecture. Recent research advances in the scaffold designing provide with a three-dimensional structure to achieve the desirable result. Among the scaffold materials available, those which are specific to BTE can be categorized into metals, glass ceramics, ceramics, natural as well as synthetic polymers, and composite materials.[7] Scaffold as a biomaterial should have good biocompatibility, biodegradability, and ability to integrate additional factors for a better regeneration of the desired structures. Among the available scaffold materials, hydrogels have porous structure like that of the extracellular matrix (ECM) and can be used as a vehicle for various factors facilitating growth factor promotion in BTE.[8910] This article presents an overview about the hydrogels and their role in BTE.

HYDROGELS

The term “Hydrogel” was coined in 1894 to explain a colloidal gel of inorganic salts. Afterward, subsequent development in this field led to many discoveries and innovations. The first biomedical application of hydrogels was reported in 1960 using poly (2-hydroxyethylmethacrylate [HEMA]) for fabricating contact lenses, which then progressed further to the present stage.

Hydrogels are three-dimensional networks composed of cross-linked hydrophilic polymers by means of covalent bonds or bonded together because of physical intramolecular and intermolecular attractions. Hydrogels have the ability to absorb huge quantity of water or biological fluids resulting in swelling which is responsible for the soft and rubbery character bearing a close resemblance to the living tissues. Hydrogels are termed as “Xerogels” in their dried form. The term “Aerogels” are dedicated to dry porous hydrogels which result using drying techniques such as solvent extraction or freeze-drying.[11] Hydrogels are also termed “smart gels” owing to their sensitivity toward external stimuli such as pH, ionic strength, and temperature, which make them highly efficient in various fields.[12] They present with tunable properties, and hence, they can be tailor made to present with the desired output.

EVOLUTION OF HYDROGELS[5]

First-generation hydrogels

The first biomedical application of hydrogels is by Wichterle and Lim in 1960 using poly (HEMA) in fabricating contact lenses. They are relatively simple synthetic polymers with chemically cross-linked polymers.

Second-generation hydrogels

These hydrogels are stimulus-responsive hydrogels, by responding to a change in the conditions of the environment.

Third-generation hydrogels

The cross-linking methods were established by means of physical interactions, hence, fine tuning their physical properties.

Fourth-generation hydrogels

These are smart hydrogels with tailored properties to provide with a promising result in stability as well as release kinetics thereby making their use a successful one in targeted delivery.

HYDROGELS AS SCAFFOLDS

The key functions of these scaffolds are to (a) deliver the seeded cells to the desired site in the patient's body, (b) encourage cell-biomaterial interactions, (c) promote cell adhesion, (d) permit adequate transport of gases, nutrients, and growth factors to ensure cell survival, vascularization, proliferation, and differentiation, (e) confer a negligible inflammation or toxicity in vivo, and (f) control the structure and function of the engineered tissue.[13]

CLASSIFICATION OF HYDROGELS

Hydrogels are classified based on their different properties as follows [Figure 1][514]

Figure 1

Classification of hydrogels based on their properties

Origin: natural (e.g.: alginate, chitosan etc.), synthetic (e.g.: PEG, PCL polycaprolactone), and hybrid (e.g.: 2-hydroxypropyl methacrylamide)

Polymeric composition: homopolymer (e.g.: polyethylene glycol based), copolymer (carboxymethyl cellulose, carboxymethyl chitosan based), multipolymer (e.g.: poly (acrylic acid-2-HEMA)/gelatin, semi-interpenetrating network (semi-IPN) (e.g.: acrylamide/acrylic acid copolymer hydrogels containing polyallylammonium chloride), interpenetrating network

Ionic charge: neutral (nonionic), ionic, amphoteric, zwitterionic

Pore size: nonporous, microporous and super porous

Physical appearance: MATRIX, film, or microspheres

Configuration: amorphous (noncrystalline), semi-crystalline, crystalline

Cross-linking: physical and chemical

Response: chemically responsive, biochemically responsive, and physically responsive.

TECHNICAL FEATURES OF HYDROGELS

Technical or functional features of hydrogel material which make them ideal are, they, have highest absorption capacity in saline, very cheap cost, pH neutral after swelling into water, show highest absorbance capacity under load, have lowest soluble content and lowest residual monomer, provide the desired rate of absorption based on requisite of application, and high stability and durability during storage; following degradation, hydrogels show high biodegradability (no toxic species formed), are nontoxic, colorless, and odorless, show high photostability, and possess rewetting capability depending on the applications.[15]

Numerous approaches and various TE techniques are feasible using hydrogels in fabricating tissue constructs with variable cell gradients and zonal structures. Techniques available for the processing of hydrogels to desirable constructs include stereolithography, biopatterning, a combination of photopatterning and electropatterning, 3D bioprinting, laser-induced forward transfer bioprinting, microextrusion bioprinting, electrospinning technology, microfluidic and micromolding techniques,[16] gas foaming, and solvent casting.[17]

MECHANICAL CHARACTERIZATION OF HYDROGELS

Optimal mechanical characterization of hydrogel-based biomaterials is an important aspect in TE to withstand wide variety of situations and paving their way for clinical translation. Various mechanical properties that should be considered in fabricating scaffold in BTE include tensile, compression and flexural properties, behavior of swelling or deswelling, indentation, pore size, pore morphology, and interpore degree of connection.[16] Techniques available to evaluate the mechanical properties of scaffolds should be nondestructive to maintain the viability, which can be achieved by techniques utilizing long focal microscopy, atomic force microscopes, and optical coherence tomography.[18] Adequate characterization of the hydrogel scaffolds is essential to increase the reliability and reproducibility in both in vitro and in vivo applications.

FORTIFIED HYDROGELS – BRIDLING THE CHALLENGES

Although hydrogels present with several advantages in TE applications, it also has several drawbacks which include poor mechanical strength thereby restricting its use in areas of load-bearing application, biodegradation behavior resulting in generation of by-products which are acidic in nature, and absence of cell binding sites which is commonly observed while using synthetic polymers.[19]

These drawbacks can be addressed by either chemical modification while processing or incorporation of inorganic fillers to polymeric matrices helps to enhance the mechanical stability. Increased tensile strength and shape recovery along with dissipation of energy while under stress produces promising results in TE, which can be achieved by incorporating additional physical cross-linking points.[19] Commonly used inorganic nanoparticles include glasses, polycrystalline ceramics, bioactive ceramics, and salts and can also be infused with additional ions such as zinc, magnesium, and copper to overcome the shortcomings.[2021]

Inorganic particle incorporation with the hydrogels aids in behavioral modification of the hydrogels by increasing specific surface area, highly porous structure, high protein adsorption, increasing the number of cells binding sites, controlling the direction, cellular growth organization, affecting the cell growth, and proliferation.[2223] The process of dissociation of inorganic materials results in release of ions, and they have significant effects on cell proliferation, differentiation, gene expression, and mineralization of the ECM.[21] Imparting strength and stiffening, the hydrogel matrix is achieved by incorporating rigid nanoparticles and altering the nanotopographic features.

Although addition of inorganic materials results in an improved physical structure of the hydrogels, they also present with certain disadvantages such as less mechanical stability and dissolution of harmful substance to the neighboring cells. This can be avoided by combining inorganic fillers with polymeric carriers.[2425]

HYDROGEL IN BONE TISSUE ENGINEERING

The field of BTE has evolved rapidly in the recent times. Despite the availability of wide range of biomaterials for BTE, hydrogel remains the choice of material in BTE because of their good biocompatibility and structural similarity to the porous ECM. In BTE, injectable form of hydrogels is preferred form as they could follow the defective cavity when placed inside, thereby filling irregular and/or large defects. Scaffold geometry which includes curvature, pore geometry, pore size, and porosity plays a role in supporting, stimulating, and guiding the process of bone formation.[26] Designing a composite scaffold material by incorporating both hydrogel and organic/inorganic fillers results in a scaffold with superior properties both mechanically and biologically.

Examples of composite systems utilized in BTE include poly (ethylene glycol) diacrylate and clay, Oligo (poly (ethylene glycol) fumarate) and calcium phosphate (apatite), cyclic acetal hydrogels and nano-HAP (hydroxyapatite), alginate and 45S5 bioactive glass (BG), gelatin methacrylate and HAP, elastin-like polypeptide collagen and 45S5 BG, and carbon nanotube chain Carbon nanotubes (CNTs).[19272829303132] The primary aim of incorporating composites into hydrogel is to maintain the granule cohesiveness, both during injection and after delivering into the defective site. The main advantage in using hydrogels is its ability to gel in situ in response to a stimulus which can be physical, chemical, temperature, or pH related.[23334] Although injectable hydrogels are superior in several aspects of bone repair and regeneration, it also poses certain drawbacks related to gelation timing, biomechanical compatibility, and function at the tissue level, resulting in mechanical damage and cracks in the surrounding tissue thereby restraining the hydrogels to sustain with their function for a prolonged period. The innovation of shape memory and self-healing hydrogels paved a way to overcome the drawback and hence resulting in restoring the original morphology by conserving cell viability and function of the tissues.[35]

CONCLUSION

Although the use of hydrogels in BTE is providing a promising result with close similarity with the native tissues, it needs further research and development to regenerate a tissue similar in biological, physical, and mechanical aspects and make its way into clinical translation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.