Dr. Saloni Mistry1, Dr. Kavita Pal2, Dr. Omkar Shete3, Dr.Divya Sawant
Professor & Head, Dept. of Prosthodontics1
Scientific Officer 'E', Clinical Pharmacology Laboratory, Advanced Centre for Treatment,
Research and Education in Cancer, Kharghar, Navi Mumbai2.
Reader & Postgraduate guide3 .
Postgraduate student of Prosthodontics4,
Dr. G.D Pol Foundation’s YMT Dental College & Hospital
Hydrogels are a promising biomaterial for the therapeutic administration of cells and bioactive compounds for tissue regeneration & drug delivery in dentistry and medicine. These hydrophilic polymers can typically be divided into two groups: natural polymers derived from tissues or other sources of natural materials, and synthetic polymers produced by combining principles from organic chemistry and molecular engineering. A variety of organic and synthetic biomaterials, such as chitosan, collagen or gelatin, alginate, hyaluronic acid, heparin, chondroitin sulfate, polyethylene glycol, and polyvinyl alcohol, are used for its synthesis. For prolonged protein release, targeted drug delivery, and tissue engineering, hydrogels have become efficient because of their high biocompatibility and microporous structure with adjustable porosity in periodontal regeneration. This review aims to summarize most commonly used hydrogels in tissue engineering, emphasizing those that are studied for the regeneration of oral tissues, their biological effects, and their clinical implications in Prosthodontics.
This article summarizes the various types of hydrogels and their applications in the field of Prosthodontics. Hydrogels has been researched upon in the field of Tissue engineering and results have shown that Hydrogels have the osteoinductive and osteoconductive potential if incorporated with Osteoprogenitor cells and Bone morphogenic proteins which will make it an 16 effective Dental Implant surface coating agent, to enhance osseointegration and Bone Implant Contact. The scope of hydrogels in Prosthodontics is still in its infancy stage and it is important to nuture its growth through the way of invitro and in-vivo studies which involves physicochemical characterization, Degradation profile & Water uptake kinetics tests, Antimicrobial activity test, Antibiotic release profile tests, Biocompatibility tests, Blood interaction tests, Cytotoxicity assay, Animal trials & finally Human clinical trials to make it an authenticated concept in the revolutionizing field of Implant Prosthodontics.
Hydrogel; oral science; tissue regeneration; Drug delivery system, Dental Implant,Surface coating agent.
Mistry S, Pal K, Shete O, Sawant D: Hydrogels in dentistry – applications and advances. J Prosthodont Dent Mater 2022;3(2):13-25.
Oral health is considered an important part of general health and quality of life, and oral disease is still a major public health problem in developed countries and a growing burden for developing countries. Common oral diseases include caries, pulp necrosis, periodontitis, oral mucositis and so on. Oral science research has developed rapidly in recent years. Advances have been made in oral tissue engineering and regenerative dentistry thanks to the growing amount of research in fields such as stem cell biology, genetic, molecular engineering, and pathologies that affect the dental tissues.1 Nevertheless, regeneration is still ruled by the need for three elements that have the goal of restoring functions of affected or diseased organ tissues: ECM, which serves as a scaffold; active biomolecules, that regulate cell growth and differentiation; and mesenchymal cells, needed for the new tissue formation. Thus, in tissue engineering, regeneration will be achieved not only if a structural scaffold is provided, conferring mechanical properties, but also, inducing migration of cell populations.2 Dental biomaterials have passed from passive bioinert structures to bioactive materials that have the final goal to return form and function to oral tissues. Hydrogels (HG), have been gaining interest since they possess three-dimensional (3D) polymeric networks with characteristics similar to tissues.3 Hydrogels are 3D Hydrophilic polymer capable of absorbing large amounts of water or biological fluids. It also acts as a scaffold that can be loaded by Cells, Bioactive materials or Growth factors.2 According to Slaughter et al, Hydrogels are defined as 3D insoluble polymer matrices created from crosslinked hydrophilic homopolymers, copolymers, or macromers.5 It distinguishes itself from other biological materials by its unique characteristics in structure and performance. The polymer network formed by the hydrogel can bind water, which in turn shows good biocompatibility due to the high moisture content. When the hydrogel is combined with biological tissue, its swelling property blurs the boundary between the hydrogel and the tissue, thus reducing the foreign body reactions. In history the use of hydrogels was right from diapers, contact lenses, wound dressings, drug delivery to now the current age of improved agriculture & tissue engineering.2 According to Eelkema et al., at present, Hydrogels are used in personal care products, biomaterials, coatings, and plant fertilizers. They also are considered for future applications such as sensing, drug delivery, soft robotics, and biohybrid or biointerfacing material. When hydrogels are compared with other types of biomaterials, they are superior showing proper mechanical strength, porous structure, enhanced biocompatibility, and adjustable biodegradability.3 It has been reported that Implantation of a Chitosan Gel scaffold into a mouse femur demonstrated that it supports the formation of extracellular matrix with minimal inflammation.4 Also, potential of hydrogel gel to support new tissue formation and thus provide a promising strategy for bone tissue engineering has been documented in literature. In dentistry the use of hydrogels has been documented for bone regeneration, tissue healing and also it can be used as an effective dental implant surface coating agent.5 This article reviews the uses of hydrogels in Prosthodontics, Oral tissue engineering, Implantology and Research based studies
History of hydrogels:
The first hydrogel poly-2-hydroxyethyl methacrylate (PHEMA) was created and described in 1960 by Whichterler and Lim. They used it to make moisture-absorbing contact lenses.6 Then, in the 1980s, Lim and Sun created calcium-alginate gel composites for islet-droplet microcapsule cell embedding.7 According to Buwalda et al., there 3 have been three distinct generations of hydrogels. The first generation of hydrogels mostly consisted of gels with diverse crosslinking techniques created by chemically altering a monomer or polymer using an initiator. After this time, in the 1970s, the significance of hydrogels increased to a new level as stimuli-responsive properties were incorporated into the hydrogels, allowing second-generation hydrogels to react to a variety of highly specific stimuli, including changes in pH, temperature, or concentration of certain biomolecules in a solution. The focus switched to the creation of stereo-complexed biomaterials and hydrogels joined through physical interactions in the third-generation hydrogels. These changes prompted scientists to focus their efforts more intently on creating the current "smart hydrogels," which can be tailored to acquire specific qualities like stimulus responsiveness and adjustable mechanical and other physicochemical properties.8
BUILDING BLOCKS FOR THE PREPARATION OF INJECTABLE HYDROGELS
A variety of materials are used to create hydrogels. Generally speaking, there are two types of hydrophilic polymers that are utilized to make hydrogels: natural polymers taken from tissues or other natural sources, and synthetic polymers created utilizing organic chemistry and molecular engineering concepts. Building blocks of synthetic and biocompatible natural polymers are used to create the injectable hydrogels shown in Table 2.9
Table 2: Shows biocompatible natural polymer and synthetic polymer building blocks for the preparation of injectable hydrogels
|Natural sources||Synthetic polymers|
|By using covalent or physical crosslinking (such as ionic or hydrogen bonding) to create injectable hydrogels, these organic polymers have been used as building blocks (e.g., reaction of functional groups on modified polymers)||Synthetic polymers are employed in conjunction with natural polymers or biomimetic peptides to promote cell adhesion, migration, and protein release because they lack the intrinsic biochemical cues for contact with cells.|
|Hyaluronic acid||Polyethylene glycol (PEG)|
|Chitosan||Polyvinyl alcohol (PVA)|
|Heparin||Poly N-isopropylacrylamide (PNIPAAm)|
TYPES OF HYDROGELS
Natural and synthetic biomaterials, such as chitosan, collagen or gelatin, alginate, hyaluronic acid, heparin, chondroitin sulfate, polyethylene glycol (PEG), and polyvinyl alcohol (PVA), are used to form hydrogels. Chemical techniques that use covalent crosslinking produced by enzymes, physical techniques that use weak secondary forces, chemical techniques that use photo-cross-linking, physical techniques that use Michael addition, and chemical techniques that use click chemistry can all be used to create injectable hydrogels that are ion-sensitive, pHsensitive, or temperature-sensitive.10
|Collagen based Hydrogel14||can mimic cell-cell and cell- matrix interactions in vivo andregulate more orderly cell growth||Cardiactissues, corneal and corneoscleral region, alveolar bone, and periodontal tissues. Also in the aesthetic area for filling wrinkles and facial expression lines|
|Gelatin based Hydrogel15||Protein derived from collagen used in food and pharmaceutical industries obtained from the skin, scales, bones, ligaments, and tendons of bovine and porcine livestock||Used in biomedical applications such as in themanufacture of contact lenses, matrices for tissue engineering, and systems drug administration Methacrylate gelatin Hydrogel (GelMA), is also used and polymerizes under ultraviolet light, in the presence of a photoinitiator,in a thermosetting cross- linked Hydrogel can be used as an injectable3D bioprinted scaffold through electrospun fibrousmembrane by light-inducedcrosslinking|
|Hyaluronic Acid Hydrogels16||Biopolymer that can be modified and processed to form Hydrogel for biomedical applications||Clinical use in areas such as ophthalmology, orthopedics ,oncology , gynecology, dentistry, and plastic surgery for the repair of skin (as dermal fillers) and neural tissues, , in gingival tissue , corneal tissue, for inter-articular visco supplementation and prevention of postoperative adhesions|
|Chitosan Hydrogels17||Provide mucoadhesive characteristics through interactions between opposite charges and can be combined with other synthetic polymers such as methyl acroloyl glycin (CS-MAG), acquiring photosensitive properties, with PEG, with fibrinogen and different types of proteins such as BMPs or amelogenin, among others, demonstrating a tissue binding capacity,able to control the release of many drugs or organo-specific signaling molecules.||Biomedicine, cosmetics, immunotherapy, cell therapy, and tissue engineering|
|Alginate Hydrogel18||Lack of biological activity but can be biofunctionalized for medical applications.||Drug delivery|
|AgaroseBased Hydrogel19||A linear polysaccharidefound in marine algae. Thermosensitive to a temperature between 32℃ and 40°C, which enable their use in bioprinting||Bioprinting materials in vitro and in vivo for skin,peripheral nerves, and skeletal tissue|
|Extracellular MatrixBased Hydrogel20||Can be solubilized in injectable HG by enzymatic digestion mainly by pepsin- mediated solubilization.||Tissue engineering applications such as photothrombotic cortical and other soft tissue ischemic lesion in rats and percutaneous transendocardial injections for cardiac repair|
|Keratin Hydrogels21||Structural fibrous protein associated with epithelial cells, is also found in hair, wool, claws, and nails. Influence cell behavior,allowing innate response modulation, as well as epithelial cell polarization||Promotes adhesion, proliferation, and differentiation of ad-MSCs in adipocytes, osteoblasts, vascular endothelial cells, and myocytes in vitro and improves skin wound healing in vivo|
|PeptideBased Hydrogel22||Biomedical materials that have great stability due to their self- assembly capacity, their high-water content allows an application based on infiltrates.||Can be combined with othertypes of molecules that make them suitable for biomedical applications such as drug delivery, antitumor therapy, 3D bioprinting, 3D culture neural tissue, tissue engineering, and wound healing|
|Synthetic Hydrogels23||Possess thermostabilityand durability in comparison with natural hydrogels Polylactic acid HG, Polyvinyl alcohol HG, Polyethylene glycol are few example||Tissue engineering & drugdelivery|
ROLE OF HYDROGELS IN PROSTHODONTICS
Hydrogels for Dental Tissue engineering
The combined use of cells, bioactive molecules, and scaffolds such as HG is considered the best approach to achieve tissue regeneration. Dental tissues can be damaged principally by caries and trauma, injuring enamel, dentin, or pulp. Advances in the field of HG could be beneficial to find the ideal scaffold to regenerate every lost tissue. HG can induce changes in cellular processes such as chemotaxis, proliferation, angiogenesis, biomineralization, and expression of specific tissue biomarkers, enhancing the regeneration process.
Hydrogels in Dental Implantology:
Dental implantology is one of the most attractive & dynamic fields within 9 Prosthodontics. However, in various clinical scenarios, prosthetic & biological complications like abutment screw loosening, fracture, peri-implantitis & marginal bone loss challenge the clinical success & longevity of Implant supported restorations. The number of patients affected by peri-implant diseases (PIDs) is increasing. According to their clinical manifestations, PIDs can be mainly categorized in peri-implant mucositis (PIM) and peri-implantitis (PI). PIM refers to a reversible inflammatory process that affects the soft tissues surrounding an implant, resulting in bleeding on gentle probing and, in some cases, suppuration, erythema, and swelling. The etiology of PIM is the bacterial accumulation and biofilm formation around the dental implant. On the other hand, PI presents not only with inflammation of the soft tissues but is also accompanied by a progressive bone loss that could lead to implant failure. Clinical data have shown that progression from PIM to PI is strongly associated with lack of preventive maintenance; thus, opportune treatment of PIM could prevent the progression to PI Current treatments against PIM are mainly aimed at eradicating subgingival dysbiosis and restoring homeostasis to microbial communities in the oral cavity. However, clinical data have shown that nonsurgical mechanical approaches, aimed at disinfection of the affected area, often fail due to recolonization of the periodontal or peri-implant pockets by pathogenic bacteria that perpetuate the disease. Moreover, bacterial infection and the subsequent epithelial cell death lead to the release of inflammatory cytokines and chemotactic bacterial peptides, which attract migratory neutrophils. This can worsen implant prognosis, mainly because neutrophil degranulation due to bacterial overload releases tissue-degrading enzymes into the gingival crevice that lead to further tissue trauma. As inflammation extends from the marginal gingiva into the supporting periodontal tissues, PIM could eventually progress to PI and lead to bone loss and implant failure. Therefore, therapeutic strategies that efficiently isolate the affected area to prevent the infiltration of bacteria and other unwanted cells, while also enabling the growth of bone- competent cells (i.e., compartmentalized tissue healing), could improve the clinical outcome of patients with PIDs. Modifications of the Implant surface to minimize these complications, to mediate bone osseointegration & tissue healing are research subjects of major interest. One promising approach consists of functionalizing dental implant materials by incorporating hydrogels with known biomolecules comprising of osteogenic, antibiotic controlled release systems. Additionally, hydrogels can be tailored to obtain the desired geometry for implantation according to the individual needs. The precise control over the microarchitecture, mechanical properties, and degradation rate of hydrogels make them useful alternatives for the controlled delivery of a variety of therapeutic agents in vivo.
Hydrogels in Maxillofacial Prosthodontics
Hydrogels are colourless, odourless material. Colour can be artificially modified by pigments and colouring agents acording to the hue. They are non-toxic, non-irritant, non-allergic and hence can be well supported by the host living tissue. They are bioinert and hence do not disturb the nearby biologic tissues. They are stable in light and have optimal transilluminance and hence can be used in areas which are exposed to sunlight like the maxillofacial area. It is light in weight, flexible, and these increases 11 the potential of it to be used as a maxillofacial prosthesis as these areas are more prone to natural creases and wrinkles as the natural appearances of external soft tissues are more important for aesthetics. The patient acceptance of this material hence can be improved. The rigidity of hydrogels can be altered by modifying its properties for using it in different areas of the maxillofacial region accordingly. The shelf life of the hydrogel can be extended up to 3 years by altering its physical and chemical properties and can successfully be used as the definitive maxillofacial material. It is also stable near living tissues as it permits diffusion of oxygen. Shear moduli, compressive moduli, and crosslink densities increase with increase in polyethylene glycol concentration, and the mechanical properties can also be altered by interpenetrating polymer network. This advantage can be used to improve the mechanical properties of and successfully use it as a maxillofacial material. Nano-composite gels are mainly altered hydrogels. These gels show superior mechanical properties such as increased compressive strength, tensile strength, yield stress, and this can be altered by changing or altering the crosslinking and also by reinforcing the carbon nanotube.
Current evidence of Hydrogels
|Type of hydrogel||Test||Outcome||Reference|
|Alginate-Matrigel hydrogel with bioactive glass microparticles. Matrigel was derived from basement membrane proteins extracted from mousetumor.||In vitro||The presence of Matrigel in the hydrogel composite increases the osteogenic differentiation of MSCs, despite the decrease in elasticity of the hydrogel with the addition of bioactive glass microparticles.||Sevari et al21|
|3D-printed heparinconjugated collagenmatrix encapsulating MSCs, reinforced with β-TCP nanoparticles scaffoldand functionalized with recombinanthuman bone morphogenetic protein type 2 (rhBMP-2)||In vitro||Capacity of heparinconjugated collagen matrix to maintain thebioactivity of rhBMP-2 and supportMSCs viability and osteogenic differentiation||Fahimipour et al22|
|Bacterial celluloseloaded with bone morphogenetic protein type 2 (BMP-2)||Invivo (frontal sinus lift rabbit model)||Bacterial cellulose presented excellent biocompatibility. When combined withBMP-2, Bacterial cellulose allowed bone regeneration and served as bothbarrier membrane and sustained-release drugcarrier proved through histological andimmunohistochemical Evaluation||Koike et al23|
|Chitosan-Gelatin hydrogel incorporating Nano dimensionalbioactive glass particles||In vitro (human dental pulp MSCs);In vivo (rat femur Defects)||Invitro- Compatibilityand ability to induce the crystallization ofbone-like apatite; Invivo ChitosanGelatin hydrogel incorporating 5% of nanoparticles of bioactive Glass significantly produced the greatest amount of new boneamong the tested groups||Covarubias et al24|
|Composite bisphosphonatelinked Hyaluronic acidcalcium phosphate hydrogel||In vivo (sinus lift rabbit model)||Synthetic granular calcium phosphate compound and deproteinized bovine mineral graft induced more bone regeneration than hyaluronic acid-calcium phosphate hydrogel at a histomorphometric Evaluation||Trbakovic et al25|
|Gelatin-coated β-tricalcium phosphate (βTCP) scaffolds with rhBMP-2-loaded chitosan nanoparticles delivery system||In vitro (human Buccal fat pad MSCs)||Gelatin-coated βTCP scaffolds with rhBMP-2- loaded chitosan nanoparticles were able to support cell viability and attachment and slowly release of rhBMP-2 in a therapeutic dose that permitted osteogenic differentiation of MSC.||Bastami et al26|
|Alginate-gelatin methacrylate (GelMA) Hydrogel||In vitro (human gingival MSCs and human bone marrow MSCs||The saddition of GelMA to alginate jeopardizes the hydrogel osteogenic differentiation induction of encapsulated MSCs, which is attributed to the decrease in the elasticity of the hydrogel.The osteogenic differentiation capacity of MSCs is regulated by the alginate-GelMA physiochemical properties and the presence of inductive signals||Ansari et al27|
|3D-bioprinted biphasic osteon-like scaffold, containing hMSCs and Human umbilical vein number of blood vessels per area (capacity to improve the neovascularization) in the bioprinted osteon-like scaffolds||In vitro (commercial hMSCs and HUVECs) In vivo (rat cranial bone defects)||In vivo: histological analysis of explanted scaffolds showed a significant increase in the number of blood vessels per area (capacity to improve the neovascularization) in the bioprinted osteon-like scaffolds||Piard et al28|
|3D polyvinyl alcoholtetraethylorthosilicatealginate-calcium oxide Biocomposite cryogels||In vivo (rat cranial bone defects)||Promotion of regeneration of the bone defect while simultaneously resorption of its contents from the defect site over the period of 4 weeks. Osteoblastic activity at the defect site with an increase of the differentiation towards osteoblastic lineage and maturation of osteoblasts from 2 to 4 weeks||Mishra et al29|
This article summarizes the various types of hydrogels and their applications in the field of Prosthodontics. Hydrogels has been researched upon in the field of Tissue engineering and results have shown that Hydrogels have the osteoinductive and osteoconductive potential if incorporated with Osteoprogenitor cells and Bone morphogenic proteins which will make it an 16 effective Dental Implant surface coating agent, to enhance osseointegration and Bone Implant Contact. The scope of hydrogels in Prosthodontics is still in its infancy stage and it is important to nuture its growth through the way of invitro and in-vivo studies which involves physicochemical characterization, Degradation profile & Water uptake kinetics tests, Antimicrobial activity test, Antibiotic release profile tests, Biocompatibility tests, Blood interaction tests, Cytotoxicity assay, Animal trials & finally Human clinical trials to make it an authenticated concept in the revolutionizing field of Implant Prosthodontics
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