Biomedical Application, Patent Repository, Clinical Trial and Regulatory Updates on Hydrogel: An Extensive Review

Hydrogels are known for their leading role in biomaterial systems involving pharmaceuticals that fascinate material scientists to work on the wide variety of biomedical applications. The physical and mechanical properties of hydrogels, along with their biodegradability and biocompatibility characteristics, have made them an attractive and flexible tool with various applications such as imaging, diagnosis and treatment. The water-cherishing nature of hydrogels and their capacity to swell—contingent upon a few ecological signals or the simple presence of water—is alluring for drug conveyance applications. Currently, there are several problems relating to drug delivery, to which hydrogel may provide a possible solution. Hence, it is pertinent to collate updates on hydrogels pertaining to biomedical applications. The primary objective of this review article is to garner information regarding classification, properties, methods of preparations, and of the polymers used with particular emphasis on injectable hydrogels. This review also covers the regulatory and other commerce specific information. Further, it enlists several patents and clinical trials of hydrogels with related indications and offers a consolidated resource for all facets associated with the biomedical hydrogels.


Introduction
Hydrogels are polymeric matrices having a three-dimensional configuration that absorb water and undergo swelling but do not dissolve (short term) and facilitate the controlled drug-release into our body [1]. The high thermodynamic affinity of this class of materials towards the solvent is contributed towards its swelling property. They bear a physical resemblance to living tissues because of their significant water content and consistency. There is also a unique type of hydrogel, called as intelligent gels or smart gels. They can perceive the stimuli and respond by exhibiting changes in their physical or chemical behaviors and subsequent release of the entrapped drug. Hydrogels are widely explored as a tool for biomedical applications due to their ability to form crosslink under mild conditions coupled with high versatility, excellent biocompatibility, and permeability to oxygen, nutrient and tunable material's properties.
Hydrogels can be delegated as a tool that meets the particular necessities to focus on the medication to the specific region and control its release. Properties of a hydrogel such as hydrolytic, enzymatic and ecological play a role to control the delivery of medication with the desired objectives such as extending their drug release profile, and expanding the choice of medicaments different drug delivery applications [2]. The hydrophilic functional groups attached to the polymeric backbone of hydrogels are responsible for their affinity to absorb water. Crosslinking between the network chains is answerable for its resistance to dissolution [3]. Both natural and synthetic materials can be used in the preparation of hydrogels. Synthetic hydrogels have replaced their natural counterparts from the last few decades due to their high water-absorbing capacity, long shelf life, high gel strength, and better stability profile in sharp fluctuating temperatures. Again, well-defined structures of synthetic polymers can be modified to yield tailor-able functionality and degradability [4].
Hydrogel has a long history of evolution and has been reported upon with diverse classifications. The term hydrogel was initially coined in the year 1894 by Van Bemmelen [5]. The first-ever synthetic hydrogel poly(2-hydroxyethyl methacrylate) (pHEMA) was synthesized by scientists DuPont in 1936, and the first drug delivery hydrogel Cervidil ® for cervical ripening was launched in 1995 [5]. Since then, continuous research and development in hydrogel has led to a total of 329, 350 patents filed until today. However, the first generation of hydrogels aimed at developing artefact with high swelling and good mechanical properties with relatively simple rationale. It comprises chemical modifications of a monomer or polymer with an initiator by involving many cross-linking procedures. In comparison, the second generation of hydrogel can produce a response concerning specific stimuli, such as variations in temperature, pressure, light, magnetic fields, electrical fields, pH or concentration of specific molecules in solution. These specific stimuli can be exploited to trigger specific events. However, the third generation of hydrogels focusing on the study and development of stereo complexed materials (e.g., PEG-PLA interaction) [6,7] or formed by crosslinking due to other physical interactions [8,9]. Nowadays, research focuses on developing the so-called "smart hydrogels", polymeric matrices having a broad spectrum of tunable properties. Nevertheless, there are several difficulties associated with utilizing hydrogels such as hydrophobicity of the active ingredients, which may create problems during medication conveyance during treatment. The water-cherishing polymeric center is most likely not an ideal site to hold incongruent hydrophobic medications. Other hydrogels have frail elasticity, which occasionally causes early arrival of the medication before landing at the objective site. In recent years, research on hydrogel has been continuously increased which can be evident from the Figure 1. Further, these statistics reveal a many fold increase in the number of patent publications related to the injectable hydrogel as compared to hydrogel from the last two decades.
Hydrogel controlled medication delivers the active constituent by utilizing framework gadgets that permit diffusion of medication and discharge through a cross-section (pores) that are loaded up with water. In the supply delivery framework, the hydrogel film is covered on a medication containing center, creating sections, cases and circles or having a high medication focus on the focal point of the framework to encourage a steady medication discharge rate. While the supply delivery framework produces time-free and consistent medication discharge using the macromolecular lattice. Lattice delivery is time-subordinate medication discharge in which the underlying delivery rate is relative to the square base of time instead of being steady. The drugs are dispersed in a polymer, and when they come into contact with water or bio-fluid they will begin to swell. During swelling, it will expand, which will ease the spread of the drug along with the relaxation of the polymer chain that supports time-independent and constant drug release kinetics. The active ingredient diffuses from the dispersed drug having a higher concentration within the hydrogel to its surrounding environment with lower concentration due to the concentration gradient. This method combines both the processes of diffusion and swelling for enabling drug release [10].
where, dc/dt = change in concentration with time, c = concentration of drug in the hydrogel D(t) = diffusion coefficient ∆c = concentration gradient u = swelling capacity of the hydrogel.
The diffusion process is governed by Fick's law of diffusion which states that diffusion occurs from a region of high concentration to the low concentration: dc/dt = χd2c/dx2 (2) where χ = diffusivity, t = time x = dimension (in length) Hydrogels significantly improve the remedial result of medication conveyance and have discovered gigantic clinical use. The worldly and three-dimensional conveyance of macromolecular medications have extraordinarily improved through hydrogel used for drug delivery [2]. Even though medication conveyance utilizing hydrogels has not been liberated from difficulties, consistent upgrades are being made to distinguish the hydrogel configuration most appropriate for explicit medication delivery purposes. However, hydrogels have recently drawn great attention for use in a diversified biomedical field for various applications such as the sustained release of active medicaments, cell therapeutics, cosmetics use, tissue regeneration and wound healing, etc. The following figure, Figure 2, illustrates the application of various hydrogels used in different body parts of humans. This review brings together different aspects of the hydrogel, such as classification, properties, preparation methods, the polymer used, and applications in the biomedical field. It specifically elaborates the injectable hydrogels enlisting their formulations for mitigating diseases. Further, it emphasizes on the regulatory aspects of commercial hydrogel highlighting the information related to certain ingredients. Additionally, it encompasses This review brings together different aspects of the hydrogel, such as classification, properties, preparation methods, the polymer used, and applications in the biomedical field. It specifically elaborates the injectable hydrogels enlisting their formulations for mitigating diseases. Further, it emphasizes on the regulatory aspects of commercial hydrogel highlighting the information related to certain ingredients. Additionally, it encompasses several patents, clinical trials and existing commercial hydrogel products with related indications. This review may act as a resource for the hydrogel system concerning the biomedical area covering all the essential aspects and may pave the way to conduct future research in this particular field.

Classification of Hydrogel-Based System
There are several opinions found in the literature concerning the classification of hydrogel. They may be classified on the basis of the source from which they are obtained, physical properties, structures, crosslinking present, the ionic charge on bound groups, preparation methods and stimuli given to produce a specific response. Based on the above, the classification of the hydrogels are shown in Figure 3.

Polymers Used for Fabricating Hydrogel
Natural polymers are usually composed of components of proteins and extracellular matrix or derivatives of natural materials such as alginate, chitosan and skill fibers which makes them inherently bioactive, biodegradable, biocompatible, nontoxic and promote many cellular functions for different biomedical applications. The two drawbacks associated with natural hydrogels are that they have poor mechanical properties. Additionally, it is unclear about the correlation between the mechanical properties and polymerization or gelation conditions. Further, they offer difficulty in being manipulated as they have a high batch variation that may lead to poor reproducibility. In contrast, synthetic hydrogels are more reproducible, although their final structure can also depend on polymerization conditions, demanding rigorous control of the preparation protocol. So, it can be concluded that synthetic hydrogels offer more flexibility for altering chemical composition and mechanical properties than natural counterparts and are more prevalent. A few commonly used natural and synthetic polymers for hydrogels are enlisted in the following Table 1 [11,12].

Properties of Hydrogel
It is imperative to have a basic understanding of the gel properties so that a suitable gel delivery system can be designed. The interactions between the gel and the solute molecules can be better understood after studying the following properties.

Swelling
Hydrogels are crosslinked macromolecular polymeric networks that can swell in a liquid medium. The swelled polymer acts as a filter which allows partial diffusion of solute molecules. The polymer network is able to retain the solvent by forming a gel and will not dissolve if crosslinked. The presence of a hydrophilic functional group attached to the backbone and the difference in the osmotic pressure between the gel phase and the solvent phase is responsible for water absorption by the hydrogel. In hydrogel, the presence of water determines the overall permeation of nutrients in and out from the gel. Thermoresponsive hydrogels are one of the other categories of hydrogels having high biomedical interest. At room temperature these appear as fluid but convert into viscous gel as they get exposed to the body temperature, which lengthens their staying time, hence prolonging their release rate. They have the ability to undergo phase transition or swell/deswell at ambient alteration of temperature. Concentrate solution of poloxamer with water is one good example of thermoreversible gel widely used for tissue engineering applications nowadays [13,14]. Further, the rate and degree of swelling, controls the release patterns of drugs and solvents from hydrogel polymeric networks.
Researchers use several methods to determine the relative free and bound water contents with respect to total water content. It indicates the swelling property of the hydrogel. Some of the common techniques used for routine investigation of water content in hydrogels are: small molecular probes, DSC and proton NMR. Additionally, evaluation of swelling properties of the hydrogel serves as a measure for many of their properties such as mechanical properties, degree of crosslinking, rate of degradation and many more. Evaluation of the swelling and swollen state stability may help distinguish between crosslinked gels and the non-crosslinked original polymer [15,16].

Mechanical Properties
Generally, the mechanical property of hydrogel is linked to their water contents and cross linking density. The stiffness of the gel can be increased by increasing the degree of crosslinking or can be decreased by heating the material. An ideal hydrogel should be mechanically robust with rapid diffusion and response rate. The mechanical properties can be changed by a wide range of variables and causes, so it should be analyzed based on the aim of the study, types of material and the condition, etc. The mechanical properties of the hydrogel can be determined by texture profile analyzer or a rheometer by calculating young modulus, Poisson modulus, storage and loss moduli, etc. Currently, more efforts have been made to construct hydrogels with substantial mechanical performance. Double-network, topological, nanocomposite, macromolecular microsphere composite and supramolecular hydrogels are among the successful strategies for fabricating high-strength hydrogel. These are promising multifunctional materials having sufficient and robust mechanical properties that can be used successfully as tissue engineering scaffolds. The degree of stiffness of the hydrogel is determined based on its application area, i.e., where it has to be applied. For example, to seed osteoblast cells, a more rigid material is required than for culturing adipocytes [17]. However, materials characterization, tensile and compressive tests are basic methods for mechanical performance evaluation [18,19].

Porosity and Permeation
This is another important property that can simply indicate the presence of a void cavity inside the bulk. There may exist smaller pores within the network or may be formed in hydrogels during synthesis (by phase separation). It is beneficial to control the porosity for several applications, such as the tunable release of macromolecules, optimal cell migration in hydrogel-based scaffolds, etc. It has been found that porosity is a significant factor that influences the swelling and drug release behavior of the hydrogels [20]. The presence of a porous structure improves the drug release while non-porous hydrogels led to a very slow release. Additionally, the presence of pores can help in sustain release drugs for prolonged periods of time [21].
Porosity can be assessed by theoretical methods, such as liquid displacement method, Archimedes method, etc., with the use of optical and electronic microscopy. Some other methods such as gas pycnometer method, gas adsorption, capillary flow porosity have also been reported. One of the other important assays is X-ray microtomography [22]. Microscopy is another technique that can be used in assays involving hydrogels by which surface morphology and topography can be assessed. It involves the use of optical microscope, scanning electron microscope (SEM), transmission electron microscope (TEM), tunnelling microscope, atomic force microscopy (AFM) [23]. Additionally, thermoporometry helps to determine pore size based on melting or crystallization point of water molecules confined into the pores of hydrogels. It has advantages over other techniques, as it analyzes the sample in dried state [24][25][26]. It is based on analyzing the thermodynamic behavior of water relating to its interaction with polymers and provide a range of pore sizes in nano scale [27].

Crosslinking
Although crosslinking is not a basic property of hydrogels, it affects all the other material properties. It has some important characteristics, as it makes the hydrogel mechanically strong, and heat and erosion resistant. It may influence the rheological parameters, hydration and diffusion through skin [28]. The degree of crosslinking can be interconnected to every characteristic of a hydrogel, however the nature of crosslinking can vary a lot. The hydrogel's network can be obtained in many different ways such as physical crosslinking (by complex coacervation or ionic interaction), chemical crosslinking via crosslinker or by radiation crosslinking. By regulating the degree of crosslinking, we can control the property of the material and can optimize it for numerous applications from the same original polymer [29,30]. However, there are several disadvantages such as relatively inflexibility in their processing properties as they are insoluble and infusible [31].

Method of Preparation
Usually, hydrogels are prepared from hydrophilic monomers, but sometimes hydrophobic monomers are also used to achieve certain desirable attributes. Synthetic polymers are hydrophobic and used to provide mechanical strength and durability to the hydrogels. The main components to fabricate hydrogels are monomer, cross linker and initiator, along with water that acts as diluent to regulate the heat of the reaction. Crosslinking reactions in hydrogel can occur via different methods, such as utilizing reaction and ionizing radiation to produce free radicals that recombine, creating cross-links, entanglements, electrostatics, and crystalline formation.
Hydrogels are derived from polar monomers and undergo crosslinking reactions by linking polymer chains to form networks. Such alterations can improve the mechanical properties and viscoelasticity for numerous biomedical applications in the pharmaceutical fields. The general methods to produce physical and chemical gels are summarized in Figure 4 [32].

Applications of Hydrogel
Due to its versatility and flexibility, hydrogel possesses diversified applicati as biomedical, agriculture, sanitary diapers, dyes removal, heavy metal ions rem osensors, pH-sensors, and super-capacitors, etc. [33]. The following section inclu medical applications of hydrogels in areas of cosmetic technology, wound healing lenses, drug delivery, and tissue engineering, etc. [12,34]. Figure 5 mentions the cal applications of hydrogel. Further, this section includes a list of patents and trials (Tables 2 and 3) related to various hydrogel formulations, which give an id the current research conducted in this area. The hydrogel formulation (prepared b crosslinking process) permits electrical tion of the lacrimal gland, nasal or sinu ↑ production of tear and to treat dr Hypotonic hydrogel formulations for en-Administered into vagina An aqueous polymeric hydrogel (polo used as a barrier by forming plug and

Applications of Hydrogel
Due to its versatility and flexibility, hydrogel possesses diversified applications such as biomedical, agriculture, sanitary diapers, dyes removal, heavy metal ions removal, biosensors, pH-sensors, and super-capacitors, etc. [33]. The following section includes biomedical applications of hydrogels in areas of cosmetic technology, wound healing, contact lenses, drug delivery, and tissue engineering, etc. [12,34]. Figure 5 mentions the biomedical applications of hydrogel. Further, this section includes a list of patents and clinical trials (Tables 2 and 3) related to various hydrogel formulations, which give an idea about the current research conducted in this area.

Cosmetics Applications
Skin is the largest organ that acts as a physical and chemical barrier and protects the body. From the cosmetic point of view, skin is responsible for external appearance and is usually treated with cosmetic preparations. Skin condition depends on several factors, among which hydration of the skin is critical in maintaining its appearance and texture [35]. When the skin barrier is damaged, either due to climatic conditions and pollution or natural ageing (the genetic factors and photo-aging) it demands reconditioning. For this purpose, a range of moisturizers to re-establish the skin properties and barrier functions can be used. Stratum corneum (upper layer of the skin) can be rehydrated by three mechanisms such as by using humectants, occlusive and hydrophilic matrices. Nowadays, hydrogel is widely exploited in the cosmetics industries due to properties such as high water retention, biocompatibility, elasticity and softness [36]. These are mainly employed for skin hydration, wrinkles, pigmentation, cellulite and ageing, etc. Cosmetically these are mainly applied topically on skin, hair, and also used in oral care. Bioadhesive hydrogels are used for skincare purposes as they have advantages, such as long residence times on the site of application which ultimately reduces administration frequency. Acrylate-based hydrogel, due to its superabsorbent properties, is highly exploited to prepare hygiene products that can absorb fluids and keep moisture away from the skin, preventing diaper rash, promoting hygiene, and providing comfort.

Wound Dressings
Human skin has a unique potential for self-regeneration, owing to this, skin defects can heal spontaneously but if the defect is measuring more than a certain diameter, then it requires skin transplantation. Moreover, the wound healing process is impaired in some patients due to various conditions that lead to chronic wounds, which ultimately result in drastic conditions or even mortality [37]. Hydrogels are the most promising approach in wound healing amongst various wound dressings polymeric materials such as gauzes,    The kits including at least one nucleophilic compound/monomer unit, minimum one electrophilic compound/monomer unit, and at least one drug. Further, the therapeutic agent such as a protein or other biomolecule is capable of gelling in vivo

Cosmetics Applications
Skin is the largest organ that acts as a physical and chemical barrier and protects the body. From the cosmetic point of view, skin is responsible for external appearance and is usually treated with cosmetic preparations. Skin condition depends on several factors, among which hydration of the skin is critical in maintaining its appearance and texture [35]. When the skin barrier is damaged, either due to climatic conditions and pollution or natural ageing (the genetic factors and photo-aging) it demands reconditioning. For this purpose, a range of moisturizers to re-establish the skin properties and barrier functions can be used. Stratum corneum (upper layer of the skin) can be rehydrated by three mechanisms such as by using humectants, occlusive and hydrophilic matrices. Nowadays, hydrogel is widely exploited in the cosmetics industries due to properties such as high water retention, biocompatibility, elasticity and softness [36]. These are mainly employed for skin hydration, wrinkles, pigmentation, cellulite and ageing, etc. Cosmetically these are mainly applied topically on skin, hair, and also used in oral care. Bioadhesive hydrogels are used for skincare purposes as they have advantages, such as long residence times on the site of application which ultimately reduces administration frequency. Acrylate-based hydrogel, due to its superabsorbent properties, is highly exploited to prepare hygiene products that can absorb fluids and keep moisture away from the skin, preventing diaper rash, promoting hygiene, and providing comfort.

Wound Dressings
Human skin has a unique potential for self-regeneration, owing to this, skin defects can heal spontaneously but if the defect is measuring more than a certain diameter, then it requires skin transplantation. Moreover, the wound healing process is impaired in some patients due to various conditions that lead to chronic wounds, which ultimately result in drastic conditions or even mortality [37]. Hydrogels are the most promising approach in wound healing amongst various wound dressings polymeric materials such as gauzes, hydrocolloids, gels, hydrogels, etc. Hydrogels act as an ideal wound dressing for the management of wounds as they can provide a moist milieu in the wound site, prevent infection, help in the removal of wound exudates and mimic the native skin microenvironment for tissue regeneration. In addition, hydrogels have unique features such as biocompatibility, softness and malleability which make them fit for the purpose. Polysaccharides based on hydrogel (cellulose, dextran, agarose) have greater water absorption capability, making them ideal candidates in wound healing [38]. However anti-bacterial and anti-inflammatory hydrogels have a good impact in wound healing [39][40][41].

Drug Delivery
Drug delivery can be defined as the process of administering a drug to a human or animal to achieve a desired therapeutic effect at an effective rate at the targeted site [42]. Delivery of the drug in a controlled manner at the particular target for an extended period is another important requirement of a good delivery system. Hydrogels, due to their threedimensional release the drug in a controlled manner, especially for hydrophilic moieties. The porosity of the hydrogel further supports the sustained action of the drug [43].It also has a great potential for application via different routes. When the hydrogel is transplanted and injected or into an organism, it can maintain an embedded drug's effective and controlled release into body fluids [44]. The hydrogel can improve the therapeutic effects of many lipophilic drugs that are restricted due to various problems, including poor solubility, poor dispersion, poor dissolution, low bioavailability, lack of uniformity, and lack of in vivo stability, etc. However, its fabrication is a difficult task and can be improved by the amalgamation of molecules having the ability to form inclusion complexes by incorporating the hydrophobic moieties [2,45]. Hydrogels can also be used as a carrier for biological macromolecular drugs, polysaccharide substances and genes, etc., without affecting the release kinetics. It follows different drug release models such as swelling controlled, diffusion-controlled and chemically controlled to release the medicaments in a controlled manner that act as release drives for the system [46].
Among diverse delivery systems injectable hydrogels are one of the extensively investigated scaffolds or therapeutic agents carriers in the area of disease treatment.

Injectable Hydrogels for Disease Treatment
Due to numerous advantages of the hydrogel systems, they have been considered suitable scaffolds or active ingredients carriers [47]. However, it requires an invasive surgical procedure for implanting pre-formed hydrogels at a specific site in the body associated with pain and discomfort in the patients, that leads to decreased patient compliance and increased treatment costs; thus, limiting their clinical uses. Injectable hydrogels can overcome such disadvantages in biomedical applications with minimal invasiveness into target sites. These hydrogels can be exploited as a promising and efficacious material system for many applications in the medical field, such as treatment for cancers, inflammatory and infectious diseases; delivery of drugs, cells, and bioactive molecules and applications in the repair and regeneration of tissues such as skin, muscles, bone and cartilage [48]. Table 4 enlists various injectable hydrogels with biomedical applications.
Injectable hydrogels involve the sol-gel transition produced by cross-linking. For solutions of a polymer/monomer with therapeutic agents that have low viscosity when administrated to a desired site in the body, a hydrogel loaded with a therapeutic agent can be formed by crosslinking reaction that has a comparatively higher viscosity, called a gel state. The polymers in the hydrogel form a cross-link by chemical or physical interactions which are responsible for phase transition from solution to gel state. The solgel phase transition is sensitive to changes in pH, temperature, light, enzymes, ultrasounds, etc. [49][50][51]. Physical crosslinking occurs due to electrostatic ionic and hydrogen bond interactions, π-interactions, hydrophobic interactions, Van der Waals forces, etc. In contrast, chemical crosslinking occurs due to Schiff base reactions, Diels-Alder reactions, photo polymerizations, Michael additions, enzyme-mediations, etc.
Recently, the delivery of chemotherapeutics in the form of injectable hydrogels became a promising alternative for cancer/tumor management with biocompatibility, enhanced drug loading, prolonged and controlled drug release, with explicit stimuli sensitivity. Injectable hydrogel can be used as a flexible tool to reach some areas that cannot be easily touched by surgery. Furthermore, hydrogel can be used as a platform for tissue repair (tissue engineering [52][53][54]) and prevent postoperative tumor recurrence. Injectable biodegradable hydrogels that can form gels in situ have been widely utilized for biomedical applications. Additionally, these hydrogels can be biofunctionalized by targeting moieties that have an affinity for overexpressed and/or unique tumor cell markers for targeted drug delivery applications [55].
Hydrogels have been used as a substitute for conventional cancer therapy, which is frequently associated with various factors such as unwanted toxicity to normal tissues, gigantic tissue loss, and unanticipated recurrence during or after the treatment. Localized drug delivery techniques (such as hydrogels [56], liposomes, nano/microparticles [57][58][59], micelles [8,60] offer localized sustained release of the chemotherapeutic. It results in increased efficacy of the treatment with minimal tissue toxicity by circumventing systemic circulation of the chemotherapeutic agents. They further facilitate high drug loading, improve solubility, and sustain drug release at the desire treatment location. Several systems have been explored for this purpose. The following Figure 6 depicts an overview of injectable hydrogel. pH-sensitive poly(lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers

Herceptin
Breast cancer -SK-BR-3 tumor bearing mice Great potential for preventing the relapse of HER2+ breast tumors after breast-conserving surgery with ↑ therapeutic efficacy, ↓ side effects and ↑ patient compliance [63]   Successfully stop the expression of matrix metalloproteinases, prevent the fibrosis process and reverse IDD in animal models [85]  Significantly ↑ the angiogenesis and new blood vessels formation by regulating the sustained release of NO and redox equilibrium in animal model. It has a ↑ potential in preventing and treating diseases [91] Gels 2021, 7, x FOR PEER REVIEW 22 of 36 Figure 6. An overview of various aspects of injectable hydrogels.

Tissue Engineering and Regenerative Medicine
Tissue engineering is a biomedical engineering discipline that refers to the practice of combining biologically active molecules, cells, and scaffolds into functional tissues. The main objective of tissue engineering is to accumulate biological substitutes that restore, repair, maintain, or improve injured tissues or whole organs. The scaffold resembles the

Tissue Engineering and Regenerative Medicine
Tissue engineering is a biomedical engineering discipline that refers to the practice of combining biologically active molecules, cells, and scaffolds into functional tissues. The main objective of tissue engineering is to accumulate biological substitutes that restore, repair, maintain, or improve injured tissues or whole organs. The scaffold resembles the extracellular matrix composed of porous structure responsible for supply of nutrients, cell growth and waste removal and thus aids tissue regeneration. In addition, the scaffolds should possess the desired quality attributes such as biocompatibility, biodegradability, mechanical strength and the ability to be sterilized. These characteristics are necessary for providing structural support to the cell and help in the process of cell growth and differentiation [92].
Regenerative medicine is a broad field where the body uses its own systems, occasionally with help foreign biological material to reconstruct cells and restructure tissues and organs. The terms "tissue engineering" and "regenerative medicine" can be used interchangeably, as the field focuses on cures instead of treatments for complex, often chronic diseases [34].
Although these areas currently play a relatively small role inpatient's treatment due to lack of reproducibility and high cost but have a greater perspective in the field of drug development to screen different medications. Currently, these are used in the regeneration of cardiac tissues, cartilage, and bone [93]. Hydrogels represent a large class of materials that can function as tissue engineering to fabricate biocompatible and biodegradable cell scaffolds [94,95]. Properties of hydrogels such as structural similarities to natural extracellular matrix, delicacy and flexibility akin to soft tissue and ability to inject easily inside the body to form irregular non flowing gels are made it useful as a scaffold material in tissue engineering. The ability of the hydrogel to show electrical conductivity also plays an excellent role in tissue engineering [96]. Lyophilization, photolithography, microfluidic, micro molding, emulsification, solvent casting-leaching, gas foaming-leaching, and 3D printing are some approaches for the production of hydrogel scaffold [97].

Hydrogel Machines
The unique properties of hydrogels, make them suitable candidate for fabricating different hydrogel machines for biomedical applications such as sensors, actuators, optics, coatings, electronics, etc. [98,99]. The basic requirement for this is the robustness of the hydrogels in terms of mechanical performance and functionality to ensure the stable operation of hydrogel machines. Recent innovations in the design of tough hydrogels [100,101], tough adhesion of hydrogels to other engineering materials, and advanced fabrication methods for hydrogels [102] have made hydrogels a promising material candidate for the next-generation machines [99].

Biosensor
A sensor can be defined as a machine or part of it that detects and responds to signals in the environments [103]. Conventional sensors, (electronic sensors and electrochemical sensors) convert environmental inputs to electrical outputs based on semiconductors and/or metallic electrodes; whereas, hydrogel sensors are based on exclusive characteristics of hydrogels, such as high water content, stimuli-responsiveness, high compliance, and high permeability to a wide range of molecules. They can be classified into two types: (a) stimuli-responsive hydrogels (that can exhibit according to environmental inputs) [104,105]; and (b) passive hydrogels (as matrices to host responsive substances such as free ions, nanoparticles, biomolecules, and living cells, etc. that respond to environmental inputs). Hydrogel sensors are becoming practical tools for diverse applications including point-of-care detection, medical diagnostics, and environmental monitoring, etc. [105].

Actuator
An actuator can be defined as a machine or a part of it that converts other forms of energy into mechanical energy to produce forces and motions. Conventional actuators adapted for mechanical systems usually contain metals and ceramics, and their actuation usually depends on relatively small deformations of the rigid materials [106]. Whereas hydrogel actuators provide mechanical motions commonly driven by relatively large deformations of the hydrogels [107]. Hydrogel actuators can be divided into three types such as (a) stimuli-responsive hydrogels driven by osmotic pressure change; (b) hydrogels matrices incorporating active elements (such as magnetic particles or free ions) in response to varying external fields (such as magnetic or electric fields); and (c) hydrogel structures with chambers.

Coatings
In the human body, many tissues and organs are covered with hydrogel coatings, resulting in extremely slippery selectively permeable surfaces. For example, articular cartilage on bones provides a lubricated surface for smooth joint movement [108]. Similarly, when rigid machines such as orthopedic implants, neural probes, cardiac sleeves, glucose sensors, needles, catheters, ultrasound transducers, and electrodes for electroencephalogram, electromyogram, electrocardiogram, and transcutaneous electrical nerve stimulation come into direct contact with the human body, hydrogel coatings can potentially provide a biocompatible interface with minimal mechanical mismatch and foreign body responses. In order to coat hydrogels on engineering materials, including metals, ceramics, glass, and elastomers, adhesion needs to form between the hydrogels and engineering materials. According to different mechanisms of hydrogel adhesion, we classify hydrogel coatings into four types: (a) physical attached [109] (b) covalent anchored (c) interracially interpenetrated, and (d) mechanically interlocked [110] hydrogel coatings.

Optics
Light and optical techniques have found particular importance in diagnosis, imaging, surgery, therapy, and many other biological types of research. Hydrogels is an ideal material for optic devices due to the above-discussed uniqueness, especially for those in close contact with biological organisms. There are two factors such as high transparency (low light absorption and scattering) and high refractive index (low bending loss) on which the effectiveness of hydrogel optics depends. According to their applications, there are four representative types of hydrogel optics developed so far, including (a) ophthalmic lenses [111], (b) smart windows and displays, (c) optical fibers [112], and (d) bioassay matrices [113].
Contact lenses are delicate ophthalmic tools that get direct contact with the eyes and are used to correct the vision, for cosmetic use imparting aesthetic effects and to deliver the active constituents for ophthalmic conditions [114]. Biocompatibility and permeability are two key properties to be considered during design besides comfort, permeable to ions for maintaining movement, continuous tear film for clear vision, non-irritable and resistance to tear film accumulation. Cornea needs oxygen for its proper functioning and therefore oxygen permeability is essential. Oxygen permeability is a very important property [115]. Principally there are two types of contact lenses, as rigid and soft contact lens.
Rigid contact lenses are typically made up of polymethyl methacrylate polymers which gives it properties such as wettability, elasticity and durability but lack of oxygen permeability. However a soft or hydrogel (poly(2-hydroxyethyl methacrylate) crosslinked with ethylene glycol dimethacrylate or silicone [116] having properties such as the ability to permeate water and oxygen with relatively high water content and good thermal and chemical stability [117]. They have the potential to assist in the treatment of various eye diseases, which is the reason why hydrogels are highly exploited as an important raw material for preparing contact lenses [118].

Hydrogel Electronics
Due to their similarities to biological tissues and versatility in electrical, mechanical, and bifunctional engineering, hydrogels have recently attracted growing attention in bioelectronics to potentially provide a seamless interface between biology and electronics. Hydrogels are generally considered electrical insulators due to the absence of mobile charges or charge carriers. The electrical conductivity of hydrogels in the physiologically relevant conditions is similar to that of tissue media, and much inferior to common electronic conductors such as metals, limiting their applications in electronics [119]. To overcome such limitation and enable the possibility of hydrogel electronics for improved tissue-electrode interfaces, a few strategies have been developed to enhance the electrical conductivity of hydrogels, including (a) the addition of ionic salts in the hydrogels to achieve ionically conductive hydrogels (b) incorporation of electrically conductive micro-and nano-materials within hydrogel matrices to endow electronic conductivity [120,121], and (c) introduction of conducting polymers into hydrogels to enhance electronic conductivity [122,123].
The Table 5 depicts various commercially available hydrogel products with their respective indications which give an idea about the applicability of hydrogel in various field and pave the way for future research.

Regulatory Aspects of Hydrogel and Its Components
The diversified raw materials employed to develop hydrogel scaffolds make their regulatory arrangement and approval challenging. Unlike drugs which are broadly classified, hydrogels are classified under the "devices" category according to Section 201(g) of the FD&C Act. Furthermore, other than a few exceptions, most hydrogel-based products are required to undergo additional FDA review of a 510(k) pre-market notification submission for obtaining legal marketing rights in the United States, which takes many years to get regulatory approval. However, according to the new European regulation, hydrogels are considered as medical device class III, and it should be taken into consideration throughout the entire lifecycle of the hydrogel, starting from the material and machine qualification to scale-up. Table 6 enlists some regulatory information of hydrogel ingredients used for the manufacturing of hydrogels.
The commission regulation (EU) N0 722/2012 of 8 August 2012, concerning particular requirements as regards the requirements laid down in Council Directives 90/385/EEC and 93/42/EEC. These were concerning active implantable medical devices and medical devices manufactured utilizing tissues of animal origin, has adopted a regulation based on: The original requirements, the maintenance of a high level of safety and health protection against the risk of transmitting animal spongiform encephalopathies. The regulation also considers that class III's active implantable medical devices and medical devices are subject to the conformity assessment procedures before being placed on the market or put into service, demanding the adoption of more detailed specifications relating to the risk analysis and management. The regulation establishes particular requirements concerning the placing on the market and/or putting into service of medical devices, including active implantable medical devices, manufactured utilizing animal tissue and their derivatives, originating from bovine, ovine and caprine species, deer, elk, mink and cats. In the case of collagen, gelatin and tallow used for the manufacturing of medical devices they shall meet at least the requirements as fit for human consumption. The regulation also establishes that the manufacturer of medical devices or his authorized representative shall carry out the risk analysis and risk management scheme before applying a conformity assessment. The member states shall verify that bodies have up-to-date knowledge of the medical devices to assess the conformity of those devices, and shall take all necessary steps to ensure that medical devices are placed on the market and/or put into service only if they comply with the current provisions and the particular requirements laid down in this regulation. Conformity assessment procedures for medical devices shall include the evaluation of compliance of the devices with the essential requirements into the current directives and the particular requirements laid down in this regulation. The manufacturer shall collect, evaluate and submit to the notified body information concerning changes regarding the animal tissue or derivatives used for the device or regarding the risk of the device. These new regulations represent an imperative change in the medical devices field and will necessitate stringent obligations to all market operators, which results in an increase in transparency and traceability guarantees of the product further leading to safety and reliability [155,156].
As hydrogels are considered a medical device class III by the new European regulation, this regulation must be considered not only in the scale-up process but also in the initial phases of the material's and the machine's invention. The regulation also considers that the active implantable medical devices and medical devices of class III are subject to the conformity assessment procedures before being placed on the market or put into service, demanding the adoption of more detailed specifications relating to the risk analysis and management. It is also considered for the elaboration of the regulation, the convenience of laying down additional provisions on the use of animal by-products not intended for human consumption, the adoption of several opinions on specified risk materials and on minimizing the risk of transmitting animal spongiform encephalopathy agents. The regulation considers that it is appropriate for the member states to verify that the notified bodies, designated to assess the conformity of those medical devices, have all the necessary expertise and up-to-date knowledge to perform this task. The period for scrutiny granted to the competent authorities of the member states concerning the notified bodies. The summary evaluation report should be shorter for medical devices manufactured using starting certified materials than in cases where uncertified materials are used. The regulation also bases its decisions on the convenience of the provision of an adequate transitional period allowing for active implantable medical devices already covered by an EC design-examination certificate or by an EC type-examination certificate to continue to be placed on the market and put into service, and that the measures provided for in this regulation are in accordance with the opinion of the Committee on Medical Device [157]. Table 6. Regulatory information about some hydrogel ingredients [158].

Conclusions
Hydrogels are a highly porous system and the polymers building them could be cross-connected to change degrees by altering their densities. Further, this porosity and the crosslinking ratio of hydrogel play a vital role in the release of medicaments. Applications of hydrogels are not simply restricted to focus medication conveyance they additionally discover applications in cleanliness items, wound dressings, contact focal points, tissue and machine designing. Further, it uses "smart" polymers capable of responding to various ecological signals permits administration of polymeric solution and undergo gelation under physiological conditions leading to in-situ hydrogels formation. However, preformed hydrogels are conventionally used for various applications as wound scaffolds; having the ability to release antimicrobial or anti-inflammatory drugs and growth factors from their structure by aiding the regeneration of the tissue. Additionally, hydrogels can be functionalized with a radiopaque that provides X-ray opacity and allows them to be used as biomedical implants for in vivo visualization and evaluation of the ability to prevent postoperative adhesions. Hydrogels are very versatile allowing varieties of the route for administrating drugs. In summary, hydrogels represent one of the most versatile technological platforms for pharmaceutical innovation.
Ongoing improvements of hydrogels in the field of focused medication conveyance have been colossal. They are altered by focusing on ligands and different polymer types that present intriguing properties for drug transportation. Ophthalmic medication conveyance is a territory seeing the huge effect in treatment from hydrogels. From agreeable contact focal points to biodegradable medication conveyance the applications in eye care have been colossal. They are 90% water, give consistent drug discharge over days or months capable of conveying little particles to huge proteins, are completely invested in conveyance and stay noticeable during checking.
It is clear that there is a lot of potential in the field of hydrogels and number of setbacks which have to be overcome. Several investigators have shown significant results for improving the efficiency of hydrogel based drug delivery system. In tissue engineering fabrication technique based on in situ crosslinked hydrogel is much appreciated. Extensive studies have been conducted, and the number of patents published in this area of hydrogels has been increasing which is promising. Therefore, over the years, hydrogels became key players in the biomedical field in general and pharmaceutical research and development in particular, employing different invasive and minimally invasive administration routes. Future research in hydrogels will concentrate on the design of 3D structures with programmed bio functionality. There is a critical need to study major factors involved in the formation of hydrogels and to establish the different physicochemical criteria for the formation of reproducible, reversible 3D hydrogel networks with precisely defined structures and properties.