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Hydrogels in Tissue Engineering: Scope and Applications Arti Vashist and Sharif Ahmad* Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India Abstract: Hydrogels have been employed as an emerging and promising tool in tissue engineering. They find application in the interdisciplinary field that applies the basic principles of biology and engineering and act as a substitute for conventional tissue engineering materials having improved and restored tissue function. This review article discusses the important characteristic properties of polymers used for the synthesis of hydrogels, which find application in tissue engineering. Furthermore, this article also reviews the recent advances and development in hydrogels used for corneal, cartilage, skin, bone and cardiac tissue for tissue engineering applications. This article highlights the future prospects and scope of hydrogels in tissue engineering.

Keywords: Biodegradable polymers, biopolymers, cartilage, drug delivery, hydrogels, scaffold, tissue engineering. 1. INTRODUCTION In recent years, millions of people are suffering from the loss or organ/ tissue failure. Advanced technologies are being used to engineer new tissues. The thrust is on the development of desired scaffold material, which serves as an extracellular matrix for the organization of cells [1]. Hydrogels have emerged as a successful tool, which finds diverse applications in the field of biomedical engineering ranging from drug delivery [2-5], contact lenses [6, 7], biosensors [8, 9], water purification techniques [10] and most importantly “Tissue engineering”. The immense potential of the three dimensional networks for tissue engineering has put forward the new vista of challenges and scope for young researchers [1, 11, 12]. The basic definition of tissue engineering can be best understood in terms of development of an alternative to tissue or organ transplantation [13]. The recent development of new biomaterials with modified properties having the capability to assimilate and form functional tissue upon implantation, has enlightened the scientific community. The demanding need of tissue engineering aroused from the severe trauma caused at a particular site challenges the natural process of tissue repair. Moreover, the scarcity in the availability of tissue, the delayed occurrence of appropriate immune response, very less available sites for excessive tissue and permanent damage at the donor site are the various crucial factors leading to the need for more advanced techniques in tissue engineering. The basic components of tissue engineering construct are the matrix, cells, and soluble factors giving rise to an integrated implantable device. The cells are seeded and encapsulated on the biodegradable hydrogel matrix, which gets degraded into a tissue like structure that can be transplanted [14]. The cells are surrounded by blood cells *Address correspondence to this author at the Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India; Tel: +91 11 26827508; Fax: +91 11 26840229; E-mail: [email protected] 1873-4316/15 $58.00+.00

and are a source of tissues with nutrients and oxygen, which help in the removal of carbon dioxide. Thus, a vascular network is required for the development of a functional tissue having exactly the similar properties and functions of the tissue to be replaced or repaired [15]. Hydrogels are an important class of materials, which have been extensively used for tissue engineering applications [16-18]. Owing to the soft tissue like surface morphology, high water content, insolubility in water, porous structure, which allow the entry of low molecular weight drugs and various nutrients, the outflow of cellular waste from the hydrogels makes them perfect candidate for tissue engineering [19, 20]. All these characteristics demonstrate their capability in encapsulation and viability of the cells. Present article gives an overview on the development of hydrogels and their applications in the field of cartilage, corneal, bone, skin and vascular tissue engineering [2125]. 2. NATURAL AND SYNTHETIC POLYMERS USED IN TISSUE ENGINEERING The basic features required for any natural or synthetic polymer used for tissue engineering are biocompatibility, biodegradability and effective mechanical strength. The list of various natural and synthetic polymers used widely in tissue engineering is shown [26, 27] in Table 1. 3. PHYSICAL AND CHEMICAL PROPERTIES OF THE POLYMERS FOR TISSUE ENGINEERING APPLICATION Natural polymers have certain characteristics by virtue of which they can perform a diverse set of functions in their native state. The current need for the development of various biomaterials, the structure and physico-chemical properties of new monomers can be tailored in accordance with the specifically required functions. Many protein based polymers are successfully applied in tissue engineering due to their © 2015 Bentham Science Publishers

Hydrogels in Tissue Engineering: Scope and Applications

Table 1.

Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 7

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List of list of various natural and synthetic polymers used widely in tissue engineering.

S. No.

Natural polymers

References

Application

Synthetic polymers

References

1.

Chitosan

[179]

Neural tissue engineering

Polyesters

[180]

Application Cardiac Tissue engineering

2.

Starch

[181]

Brain-resembling superabsorbent magnetic hydrogel

Polyorthoesters

[182]

Tissue repair

3.

Chitin

[183]

Tissue engineering for nervous system

Polyglycolic acids

[184]

Cell growth

4.

Guar gum

[185]

3D scaffolds immobilized with growth factor for tissue engineering

Polylactic acid

[26]

Tissue engineering

5.

Lignin

[186]

Ocular bandage

Polycaprolactones

[187]

Heart valve tissue engineering

6.

Cellulose

[65, 188]

Composite scaffold for tissue engineering

Poly(propylene fumarates)

[189]

Rapid proteotyping based tissue engineering

7

Lactic acid

[190]

Biomimetic material

Polyanhydrides

[26]

Tissue engineering

8

Silk Fibroin

[191]

Cartilage tissue engineering

Polycarbonates

[192]

Bone Tissue engineering

9

Gelatin

[193]

Vascular tissue engineering

Polyurethanes

[194]

Scaffolds for Tissue engineering

10

Fibrin

[195]

Scaffold for controlled delivery of bioactive pro-angiogenetic growth factors

Polyphosphazenes

[196]

Tissue engineering

11

Collagen

[197]

Neural tissue engineering

Poly ethylene glycol

[198]

Smooth muscle cell migration

resemblance with the extracellular matrix and possess the ability to direct the migration and healing process [28-30]. Moreover, they have the potential to stabilize the encapsulated and transplanted cells so that the construct integrate itself with the surrounding ECM [31]. Collagen is the major protein component of ECM and is not only a promising scaffold material but also supports the connective tissues like skin, ligaments, tendons, bones and cartilage [32-34]. It holds the potential to interact with cells of connective tissue and induces the cell differentiation, proliferation and survival [35, 36]. The excellent properties like good mechanical strength, biocompatibility and capability to be cross linked and the water-uptake properties of collagen make it a potential candidate for tissue engineering [31]. Gelatin, a commonly used biopolymer, which is derived from collagen is also used in tissue engineering [37]. Owing to its biodegradability and biocompatibility, it has been widely accepted as a sealant for vascular prostheses [38]. One of the important characteristics of gelatin is its low antigenicity. It is a denatured protein, which is manufactured by alkaline processing of collagen. The electrical behaviour of collagen greatly influences the development of gelatin with different isoelectric points. The treatments such as acidic or alkaline pre-treatment, produce electrically different gelatin. The different gelatins with varying isoelectric points are used for complexation of a gelatin carrier with both negatively or positively charged biomolecules [31]. In a recent study carried out by Daniele, et al. [39] demonstrated the development of bio/synthetic interpenetrating networks having gela-

tin methacrylamide, which was polymerized within a polyethylene glycol (PEG) network giving rise to a mechanically strong network having the capacity to support both the internal cell encapsulation and surface cell adherence. These interpenetrating networks (IPN) were found to be of great benefits for endothelial cells with extensive cytoplasmic spreading and generation of cellular adhesion sites, when cultured on a three dimensional hydrogel network. Fibrin, a non- globular protein is generally known to be involved in the clotting of blood [40]. The formation of fibrin takes place by the action of fibrinogen. Fibrinogen is a large glycoprotein that helps in the polymerization of fibrin. Fibrin gel is used in a fiber based scaffold for cardiovascular tissue engineering. The advantage of fibrin gel over conventional gels is that the cell entrapped in fibrin gel produces more collagen and elastin as compared to cells in collagen gel [41]. The main function of fibrin is to form clot over the site of wound with the help of platelets [42]. The characteristic property of this protein is that it itself carries sites of cell binding and thus used for cell adhesion, proliferation and their spreading [43]. Whenever any vascular injury takes place the formation of fibrin clots occurs, with the release of an enzyme, thrombin, a serine protease, which activates many constituents responsible for the coagulation. The other important characteristic is glue like characteristic of fibrin glue is extensively used in surgeries as a bio adhesive. It can clot the blood i.e. it is haemostatic as well has chemotactic and mitogenic characteristics [44].

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All the natural polymers like chitosan [45-47], starch [4850], cellulose [51, 52], gellan gum [53] and dextran [54] have been extensively used for various tissue engineering applications. These natural polysaccharides are chemically identical to heparin, thus all of them show good hemocompatibility [55]. Chitosan, a cationic polymer has versatile characteristics due to the presence of hydroxyl and amino groups, which can be metabolized by certain enzymes. It is bio adhesive in nature. It has unique pH sensitive swelling characteristics [56]. Porous chitosan finds great potential as a bone regenerative material. Porous chitosan materials are generally prepared by freeze drying i.e., lyophillization of chitosan solutions. It is also reported that hydrated porous chitosan membranes are more extensible as compared to non-porous membranes [57, 58]. Chitosan structurally resembles to glycosaminoglycans (GAGs), which are found in extracellular matrices in native articular cartilage and are considered to play a crucial role in controlling and handling the chondrocyte morphology and function. Thus, chitosan is an attractive material for cartilage tissue engineering [59, 60]. It is also found to increase the blood coagulation [61] hence is applied in wound healing application [62, 63] due to its cationic nature. It was also found to enhance the functions of inflammatory cells [64]. Other natural polymer used in tissue engineering is cellulose, a linear polysaccharide of Dglucose links by β -(1-4) glycosidic bonds. Its structure closely resembles to the micro fibrils having highly stable structure and having very low flexibility. This compact structure gives it a lot of strength and makes it water insoluble [65]. Regenerated cellulose hydrogels have been used as implantable material in orthopaedic surgery [66, 67]. It is extensively used in bone tissue engineering [68]. The chemically modified cellulose by phosphorylation in phosphate solution induces apatite nucleation in simulated biological fluids, thereby improving the compatibility and bonding with bone tissue [65]. PEG due to its critical properties like biocompatibility, diol structure can be easily converted to different functional groups or can be bioconjugated with bioactives and is being used in scaffold applications [69, 70]. It is one of the crucial synthetic polymers in demand due to its critical properties like good biocompatibility, resistance to protein absorption and also shows non-immunogenity for tissue engineering applications [69-71]. Moreover, its ability to get photopolymerized and flexible mechanical properties for scaffold design makes it more attractive. The polymer chain length and density can be tailored for specific transport properties [72]. PEG hydrogels have been modified by various bioactive molecules like cell adhesive molecules, cell adhesive peptides, enzyme sensitive molecules and various growth factors [71]. The different type of binding such as growth factor binding or cell binding to the PEG hydrogels gives specific functions to them. Different binding moieties provide characteristic advantages to PEG hydrogels that completely overcome the limitations associated with PEG. For example, the hydrogels synthesized from photopolymerization of PEG diacrylate (PEGDA) contains ester bond which show early degradation in vivo and in vitro. However, by the modification by introduction of PLA and PGA the degradation time can be improved [73, 74].

Vashist and Ahmad

4. SYNTHESIS PROCESS USED FOR POLYMER BASED HYDROGEL SCAFFOLD MATERIALS For the deep knowledge of synthesis process employed for hydrogel scaffold material, intense information about extracellular matrix (ECM) is required, which can support and surround the cells. The ECM is composed of interconnected mesh which is made of proteins and glycosaminoglycans (GAGs). The receptors can bind with the ECM environment and to create the construct the cells send the signals and thereby degrade the microenvironment for remodelling [75]. The basic function of ECM is to provide mechanical support to the surrounding tissues, organize and control cell behaviour [75, 76]. Various proteins like laminin, collagen, fibronectin are used for the synthesis of synthetic hydrogels [77]. Hydrogels having cell adhesive proteins are good for cell binding and can be produced at a large scale. Basically, cell adhesion molecules are proteins, which are located on the cell surface and are involved in the binding with the ECM. RGD are a common cell-adhesive peptides (CAP), which are basically integrin binding domain of laminin, collagen and fibronectin [78]. Other functional groups like amine, carboxyl, thiol and vinyl are used to functionalize peptides needed for inserting into hydrogels. The N- terminus of peptides is widely modified using acrylation [78]. Numerous techniques have been reported in the literature for the synthesis of hydrogels scaffold material, which include solvent casting [79], gas foaming [80], freeze drying [81], 3D –printing and phase separation [82, 83]. However, the limitations like nano size maintenance, tunable pore size, mechanically weak material, long processing time for complete evolution of solvent are reportedly associated with the above mentioned techniques. To overcome these limitations, many other techniques are being developed. Reverchon et al. [84] introduced an SC-CO2 gel drying process and tested it to produce 3-D scaffold with tunable macro and nano structure. In another important study by Cardea et al. [85] a supercritical gel drying method was proposed including a water/ solvent substitution step. Natural polymers like chitosan, alginate and synthetic polymer PVA was used to synthesize gels and the drying method opted showed the potential of these hydrogels of tissue engineering. For the synthesis process understanding the term “hydrogel gradients” is very important. Hydrogel gradients results when the concentration gradients of the monomers when crosslinked by photopolymerization, or thermal cross linking or by chemical crosslinking [86]. The method of photopolymerization has a complete control on the type, size and shape of hydrogel scaffolds. For example, the process of synthesis by using photo initiators controls the spatial and temporal arrangement and their shapes. Photopolymerization [87] synthesis methods are more advantageous than the conventional methods of synthesis for hydrogels as these provide fast curing rates at room temperature and use least amount of heat. Moreover in situ hydrogels are developed from aqueous precursors as this process can be carried out in the presence of living cells [87, 88]. UV technique can result in biocompatible hydrogel matrix. Crosslinking methods are importantly used to create gradients. These gradients generation methods are determining factors to recreate cellular microenvironments and are extremely useful to supply information about the cellular behaviour for tissue engineering [86].


Click chemistry has been used for osteogenic differentiation of bone marrow stromal cells [89] and the covalent bonding procedure can overcome the initial burst release of various growth factors [90]. Various growth factors, responsible for adapting cell functions like differentiation, proliferation and migration are incorporated inside the hydrogels using different methodologies like by direct loading during the formation of hydrogels. Direct loading process is advantageous and can be employed where an initial drug burst is required [91]. 5. APPLICATIONS OF POLYMERIC HYDROGELS AS SCAFFOLD MATERIAL


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other biopolymers like hydroxy propyl cellulose (HPC) [27, 102] collagen [103] and elastin [104] for tissue engineering. In another study demonstrated by Ahn et al. [105], Ncyclohexyl-N-(2-morpholinoethyl) carbodiimide metho-ptoluene sulphonate (CMC), a bulky carbodimide is a more feasible option to EDC as a crosslinker for collagen based materials used for corneal tissue engineering. Figure 2 shows the in vivo tolerability and resilience of EDC and CMC hydrogel transplants. These implants were mechanically strong to hold up trephination and suturing inside the mouse cornea and it was also seen that there was no big difference in onset of opacity and rate of extrusion for both the gels and hence confirms there potential to be used in corneal tissue engineering [105].

5.1. Hydrogels for Corneal Tissue Engineering Corneal blindness is a disease, which occurs due to functional impairment of the corneal endothelium [92]. Various biocompatible polymers such as Chitosan, PEG and collagen are employed for corneal tissue engineering [93-95]. A unique combination of properties and structure is required for an artificial cornea having an intact epithelium and tear film [96]. The artificial implant should not impose any immunologic reaction and should give same optical refraction as the native cornea [97]. Hydrogels owing to their soft rubbery tissue like structures are much demanded material for corneal tissue engineering. Rafat et al. [98], developed a collagen –chitosan composite hydrogels as corneal implants, which was stabilized by using a hybrid cross linker poly(ethylene glycol) dibutyraldehyde (PEG-DBA), A simple carbodimide, and a short range amide type cross linker like 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N-hydroxysuccinimide (NHS) were used. These hybrid hydrogels showed an increased mechanical strength and elasticity. A better permeability to glucose and albumin was also observed. These hybrids hydrogels showed better biocompatibility when implanted into pig corneas and a regeneration of host epithelium storma and nerves. In a more recent study carried out by Ozcelik et al. [99] revealed the potential of ultrathin Chitosan- poly(ethylene glycol) hydrogel films for corneal tissue engineering applications. These films possessed tensile strains and stresses identical are far more than those of normal human corneal tissue. Moreover, these films were >95% optically transparent, which was greater than the transparency of human cornea >90% (Fig. 1). These films were tested in vivo on ovine eyes, which demonstrated attachment and proliferation of ovine corneal endothelial cells (CECs). Figures 1a and 1b showed the method opted for the synthesis of chitosan films and the cross linked structure formed. The thickness of the films ~ 26µm and showed a smooth and imperfection free topology (Fig. 1c and 1d) [99]. Chitosan based hydrogel films have been extensively studied for corneal tissue engineering applications [94, 100]. Different modifications to enhance the mechanical strength of chitosan films, many crosslinkers like glutarldehyde, epicholorohydrin are used [98]. However, use of such crosslinkers induce toxicity and may affect the biocompatibility of the films. Thus biopolymeric hydrogels using compatible crosslinkers are in demand. For example, Grolik et al. [101] used genipin – crosslinked chitosan blends for corneal epithelium tissue engineering. These cross linked scaffolds were used for culturing corneal epithelium. This study also supports the use of

Fig. (1). (a) Synthesis of CPHF films. (b) Swollen CPHF with schematic showing cross-linked structure. (c) SEM images of the dehydrated CPHF cross-section and surface (note the smoothness and lack of defects). (d) CPHF50 folded in half in PBS solution. Transparency of the film makes observation with the naked eye difficult. The arrow is pointing at the location of the fold in the film to demonstrate transparency even when film thickness is doubled. “Reprinted from Ref. [99] 9/5 Berkay Ozcelik, Karl D. Brown, Anton Blencowe, Mark Daniell, Geoff W. Stevens, Greg G. Qiao, Ultrathin chitosan–poly(ethylene glycol) hydrogel films for corneal tissue engineering. 6594-6605. Copyright (2013) with permission from Elsevier.


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Fig. (2). Clinical examples of grafted hydrogels EDC/RHCIII and CMC/RHCIII in naïve BALB/c recipients at different time points postgrafting. (A, B) Day 1 post-graft; (C, D) day 14 post-graft; (E, F) day 22 post-graft. (G) The percentage of survival of EDC and CMC hydrogels over time. Fully mismatched corneal allografts served as controls. Note the clarity of the implanted hydrogel in (A–D); however, by day 22 the view of the iris through the implant is significantly reduced due to the presence of ‘‘retroimplant membrane’’ (E, F). Fully mismatched corneal allografts served as controls. “Reprinted from Crosslinked collagen hydrogels as corneal implants: Effect of stearically bulky vs. non-bulky carbodimides as crosslinkers, 9, Jae-Il Ahn, Lucia Kuffova, Kimberley Merrett, Debbie Mitra, John V. Forrester, Fengfu Li, May Griffith 7796-7805.,Copyright (2013), with permission from Elsevier [105].

Besides the use of natural polymer based hydrogels synthetic polymers are also being used explored for corneal tissue engineering. Membranes composed of hydroxypropyl chitosan based blends were being investigated for corneal tissue engineering. These membranes were found to be promising carrier of corneal cells and were capable to be used in reconstruction of cornea [106]. In one more recent study, PEGDA based hydrogels were studied in vitro using cell adhesion peptides as a platform for similar human corneal epithelium cells (HCECs). It was found that PEGDA hydrogels (Mw ~3400g/mol) presented the non-specific cell adhesion [107]. Functionalizations of these gels with integrin-binding peptide Arg-Gly-Asp (RGD) in different concentrations were used to culture HCECs which showed quite less dependency for alignment. Collagen and glycopolymer based hydrogel were explored for corneal applications[108]. The interpenetrating hydrogel network were prepared by photocuring of 6-Methacrylolyl-α-D-galactopyranose (MG) and crosslinking by poly(ethylene glycol)diacrylate and further crosslinking type I collagen with 1-ethyl-3-(3dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide. The role of MG on the tensile strength, modulus and stability was demonstrated and a suturing test was conducted on the gel which showed (Fig. 3) no tearing or microshearing of the suture points. In addition this study revealed that the mechanical strength is an important parameter and fulfils the requirement of better implant for full thickness corneal transplantation [108]. Figure 4 shows the several hydrogels used for corneal tissue engineering [95, 108-111].

Fig. (3). Digital image of CG2 hydrogel implant sutured 16 times to the rim of a human cornea. “Reprinted from ref [108] Crosslinked collagen hydrogels as corneal implants: Effects of sterically bulky vs. non-bulky carbodiimides as crosslinkers,6/1, Chao Deng,Fengfu Li,Joanne M. Hackett,Shazia H. Chaudhry,Floyd N. Toll,Baldwin Toye,William Hodge,May Griffith, 187-194, Copyright (2010), with permission from Elsevier.

5.2. Hydrogels for Skin Tissue Engineering Skin is an important organ of integumentary systems constituting of multiple layers of ectodermal tissue and acts as a protective barrier for bones, muscles, ligaments and other organs beneath it. It acts as an interface between the outer environments and is known as the first line of defence from external factors. Figure 5 shows the use of hyaluronan (HA) as a biopolymer, which is binded with bioactives for


PEG‐stabilized carbodiimide crosslinked collagen‐ chitosan [105] Hydrogel derived from decellularized porcine cornea extracellular matrix [108]

Collagen and glycopolymer based hydrogels [106]

Hydrogels for corneal tissue engineering

Gelatin based hydrogels [94]

Gelatin Nanofiber‐ Reinforced Alginate Gel Scaffolds [107]

Fig. (4). Several hydrogels used for corneal tissue engineering.

healing of cutaneous wounds [112]. The biopolymer was derivatized using thiol (HA-DTPH) and formed intermolecular crosslinked hyaluronan (xHA). Mechanical stimuli were also observed from the visco-elastic properties of xHA. It was seen that the biochemical stimuli from biomimetics xHA binded with C, H and HV are tolerant for the healing of porcine wounds. Platelet derived growth factor (PDGF) was loaded in stiff xHA, which showed a four day increase in healing [112]. Skin engineering represents a challenging concept in the treatment of acute and chronic wounds. The prominent limitations associated with it are pain and infection on the donor site when autografts and allografts are used [113]. Presently, the motive is to design the exact physiology, anatomy and other characteristic properties similar to skin. Various factors are important which are to be considered while choosing materials for this design. Such as the skin substitute, should be easy to handle, mechanically strong, biocompatible and importantly biodegradable. The conventional methods in skin tissue engineering is by growing the cells in vitro and seeded onto a scaffold or a porous material like hydrogel and then used in vivo at the site of wound [114, 115]. Hydrogels have been explored extensively for skin tissue engineering which to a great extent is clinically applied as a skin substitute. Earlier many efforts have been made to understand the cellular process at the molecular level involved in healing of acute wounds [116, 117]. Furthermore, the process of photopolymerization of hydrogels is unique technique opted for transdermal applications [87]. This technique uses the long wavelength UV light for initiation. The whole process constitutes of a precursor solution of hydrogels, which contains a photo initiator and when this solution is injected subcutaneously the solution is injected subcutaneously the solution undergoes transformation into gel by transdermal illumination. Now a days, this process is opted for visible or near IR initiations as a more prominent transmission in these wavelength is observed when passed across skin. PEG diacrylate, methacrylates, fumarates are few macromers which are being used in this technique. Chitosan


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based hydrogels have been employed in skin engineering. An interesting study carried out by Adekogbe et al. [118] demonstrated the fabrication of chitosan crosslinked with dimethyl 3-3, dithiobis propioninidate (DTBP). A comparison between the crosslinked and uncrosslinked chitosan scaffolds was done to see the influence of crosslinking for tissue engineering applications. It was found that significant pore size suitable for skin tissue engineering was obtained in the crosslinked scaffolds. Another interesting study carried out by Burkatovskaya et al. [119] illustrated the antimicrobial ability of Hem Com TM bandage, composed of chitosan acetate with alginate sponge bandage and silver sulfadiazine cream in mouse model was also performed. The study showed that chitosan acetate treated mice infected with P. aeruginosa and P. mirabilis survived (100%) while other treatments gave 25-100% mortality. Hyaluronan based hydrogels have been investigated as a construct for human adults dermal fibroblasts. Ghosh et al. [120] showed that when hyaluronan hydrogels tethered with the three fibronectin successfully showed wound healing in vivo. The hyaluronan hydrogels due to the fact that their synthesis processes require room temperature and at physiological pH diminishes the possibility of denaturation of bioactives when incorporated during the synthesis process. The other characteristic property is its ability to form gel in situ makes its dosage form easier and its favourable viscosity, which is quite similar to that of fibrin clot and normal human dermis. 5.3. Hydrogels for Cartilage Tissue Engineering Several millions of people worldwide in additions to 27 million of Americans are suffering from cartilage degeneration caused due to the osteoarthritis or more commonly trauma. It is a well known fact that the articular cartilage limits its ability to heal the degenerative diseases or any other injuries. Hence, there is an immense need for a successful regeneration approach, which can produce native cartilage extracellular matrix [121, 122]. Most importantly, articular cartilage can be repaired by tissue engineering using a scaffold material and transplanted cells. “Hydrogels” are considered as promising scaffold material due to their structural and mechanical resemblance needed for cartilage tissue engineering [11, 123] The main motive of cartilage tissue engineering is to in vitro culture the chondrocytes, which require a unique environment to maintain the phenotype. The biodendrimer based hydrogels scaffolds have emerged as successful candidate in cartilage tissue engineering [124]. Multivalent and water soluble triblock copolymer of PEG core and terminal blocks of methacrylated poly (glycerol succinic acid) has been used in cartilage engineering. These dendritic hydrogels have shown potential in chondrocyte proliferation and in vitro tissue growth of the cartilage. These scaffolds have shown dominant mechanical properties as compared to earlier reported hydrogel systems synthesized using hyaluronic acid, [90] and alginates. The basic mechanisms by which a hydrogel scaffold works can be best explained in terms of the swelling behaviour observed beyond the site of trauma. Environment leads to de-differentiation to fibroblasts. Thus the most important factor in the design of any constructs in cartilage tissue engineering is the study of environment, the collagen content, morphology and the viability. It is noteworthy that the alginate cultures provide a


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Fig. (5). Example of an acellular, functionalized, tissue-engineered biopolymer for acceleration of cutaneous wound healing. Thiolderivatized Hyaluronan (HA-DTPH) was synthesized as previously described (Shu et al., 2002). Homobifunctional poly(ethylene)glycol (PEG) derivatives were added to HA-DTPH to intermolecularly crosslink hyaluronan (xHA) and also to tether cys-tagged fibronectin functional domains (C, H, HV) to the xHA (Biomimetic tethered to xHa) (Ghosh et al., 2006b). Biochemical stimuli from biomimetics: xHA tethered with C, H, and HV was fully permissive for healing of reinjured porcine cutaneous wounds while xHA tethered with RGD peptides inhibited healing. Mechanical stimuli from xHA viscoelastic properties: Less stiff xHA (95 Pascals) failed to support full spreading of cultured fibroblasts, which showed buckling of actin bundles, while stiffer xHA (4270 Pa) supported robust spreading of fibroblasts, which showed tense actin bundles. Less stiff xHA tethered with C, H, and HV (95 Pa) did not enhance healing 4-day wounds while stiffer constructs (4270 Pa) increased granulation tissue formation by 75% at 4 days. When PDGF was preloaded in the stiffer xHA constructs tethered with C, H, HV (PDGF-preloaded scaffold), the healing of 4-day wounds was further increased to almost double the normal healing rate as judged by re-epithelialization, granulation tissue formation, and angiogenesis. In addition, xHA tethered with C, H, and HV and preloaded with PDGF promoted fibroblast migration in vitro to the same extent as PDGF in solution. Reprinted by permission from Macmillan Publishers Ltd: [Journal of Investigative Dermatology], copyright (2007) [112].

system to test the microenviornmental effects on chondrocytes. The available treatments of cartilage repair include the use of anti-inflammatory drugs, surgical interventions, which remove the affected tissues and replace it by prosthetic devices, joint fusion, and chondrocyte transplantation. Though these process show complications in long term. Figure 6 [125] demonstrate the various techniques opted for cartilage tissue engineering. It shows the use of injections into the lesions, avoiding the implantation and thus promoting the tissue growth in vivo. Another approach is by implantation of natural or synthetic scaffold material containing allogenic sources of chondroprogenitor cells or growth factors. Recently, photodendritic based hydrogel scaffold are in demand for cartilage tissue repair. An important study carried out by Sontjens et al. [124] they synthesized a hydrogel scaffold for cartilage repair using a multivalent and water

soluble triblock copolymer comprising of PEG core and methacrylated poly(glycerol succinic acid) dendrimer terminal blocks. These terminal methacrylated groups undergo photocrosslinking with visible light which in turn ease up the in vivo filling of irregularly shaped defects with dendrimer based scaffolds. Mechanical strength is the utmost parameter for any tissue engineered constructs. These constructs should be able to bear stresses within normal physiological levels (2-6 MPa or higher). Thus dynamic modulation of designed construct decides the eligibility of the construct to be applicable in cartilage tissue engineering. 5.4. Hydrogels for Cardiac Tissue Engineering The most critical and sensitive organ of human body is heart. All the nutrients supply of oxygen rich blood occurs via the construction of cardiac muscles [126]. It is an organ



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Fig. (6). Schematic representation of methods of cartilage tissue engineering. “Reprinted with permission from [125]”. Copyright (2011) American Chemical Society.

which lacks ability to regenerate the damaged heart tissue. A report by American Heart Association suggested that the cardiovascular diseases are the number one reason for deaths globally [127]. Cardiac tissue engineering involves the development of functional models of heart muscle and reconstructs the structure and function of injured myocardium [128]. Hydrogels are the potential candidate used for cardiac tissue engineering as they promote the viability and functionality of cells. Fibrin hydrogels have been used in cardiac tissue engineering. In a study carried out by Ye et al. [129] described the isolation of neonatal cardiomyocytes from the 3 day old rat pups. These cells are commonly used as cell source for in vitro studies in cardiac tissue engineering. The formation of fibrin gel was done by using fibrogen and enzyme thrombin. This enzyme cleaves the fibrinopeptides from the fibrinogen and exposing the binding sites which can interact with other monomers which subsequently causes the monomers to self assemble to form hydrogel mesh. Culturing process of cardiac cell was of 2 weeks. Remodelling of the constructs was observed by the cardiac cells. In an important study carried out by Ott et al. [130], a decellularized rat heart was used as a template for the development of a functional heart by recellularizing it with cardiomyocytes, endothelial cells (ECs) and smooth muscle cells (SMCs). This study demonstrated that an additional modification for the above decellularized matrix by the digestion process can produce a soluble ECM hydrogels having the capability to undergo in situ gelation. Hydrogels, due to their electric and thermo-responsive behaviour have emerged as a successful tool in cardiac tissue engineering. In an interesting study, tetraaniline an electroactive material was incorporated into a thermo-sensitive copolymer P(NIPAM-mPEGMA-MDO-MATA) (PN-TA)

[131]. This study demonstrated the use of electroactive hydrogel for cardiac repair. Figure 7 showed the use of this gel in SD rats. The study also demonstrated the formation of hydrogel at 1 day and 3 weeks post injection. The disappearance of the gel after 4 weeks at the injection sites was observed. This injectable hydrogel exhibited good mechanical strength and also increases the myocardial regeneration [131]. A study by Boccafoschi et al., [132] collagen based scaffold which is used for vascular tissue engineering. It was found that neutralized acid soluble type I collagen films do not enhance blood coagulation without altering visco-elastic properties of blood. 5.5. Hydrogels for Bone Tissue Engineering The various disorders of bone are increasing day by day worldwide. The regions of high population where old age people are more suffer from numerous bone diseases. For bone, many surgical procedures are involved, which make extensive use of bone grafts. A total of 5 billion dollars are spent on these bone grafts [133]. The area of bone tissue engineering has gained great attention due to the fact that the recovery or repair process is compensated in the intervening time when the patient’s own tissue is recovering with the new tissue regeneration time. Recently hydrogels have been applied for the treatment of various degenerative diseases, which include ophthalmic drug delivery systems, cartilage degenerative pathologies, cancers etc. Various biomaterials have been exploited for bone formation such as Osteoinductive materials which have the capability to induce ectopic bone formation by directing the surrounding environment [134]. Hydrogels have been explored for bone tissue engineering as it can best act as matrix for regenerative medicine as resemble the topography of extracellular matrix and can


Vashist and Ahmad

Fig. (7). In vivo hydrogel formation in the subcutaneous tissue at different intervals (a) 1 day and (b) 3 weeks, and (c) images of HE- stained slices of surrounding tissues at indicated days for examination of the inflammation reaction (L: lymphocytes; M: macrophages; and N: neutrophils). “Reprinted with permission from [131]” Copyright (2014) American Chemical Society.

be used to deliver the bioactive agent required for bone tissue regeneration [135, 136]. Hydrogels nanocomposite are also recently being studied for bone tissue engineering [137, 138]. It is well known fact that the mechanical strength of human bone is of the utmost importance. Nanofillers likes Carbon nanotubes(CNT) [139], fume silica [140, 141], graphene oxide [142, 143] and clay [144, 145] TiO2 are being studied [146]. A study demonstrated that a composite CNT and poly(lactic-co-glycolic acid) (PLGA) microspheres scaffold showed an increased biomimetic biomineralization in simulated biological fluids (SBF) [147]. Another study carried out by Dessi et al. [148] demonstrated the use of novel biomimetic thermosensitive injectable hydrogels composed of β -tricalcium phosphate/ Chitosan- based hydrogels for hard tissue regeneration rheological analysis, showed gel behaviour and an elastic character owing to the 3D-network. This material had potential to enhance the cell proliferation and cellular adhesion. Hydrogels have been modified using various filler like hydroxyapatite [146, 149]. Calcium carbonate or dimineralized bone matrix [150, 151] renders mechanical strength as well as cell attachment properties. Intensive work has been done to covalently incorporate cell membrane receptor peptide ligand inside the hydrogels for better adhesion, spreading of cell as well as their growth [152]. Thomas et al. investigated the inclusion of macropores into hydrogels synthesized from PEG. Lentivirus was loaded inside the hydrogels so that the activity of this virus is retained. These macropores enhanced the cell infiltration, transduction and also influences the tissue development [153]. Hybrid hydrogels are also developed for specific application Fume silica modified 2-hydroxyethyl methacrylate hydrogels showed better adhesion and cell proliferation [154]. Synthetic degradable polymers based hydrogels like polyorthoesters are very useful in orthopaedic applications [155157]. These polymers exhibit a tunable degradable characteristic and with the addition of lactides segments desired deg-

radation time can be obtained [158, 159]. It is well known fact that the natural bone apatite crystals are bounded with citrate rich molecules. In a recent study by Gyawali et al., [160] demonstrated the use of an injectable composite for bone defects and demonstrated its potential in cell delivery carrier for bone tissue engineering. The PEG Monoacrylate/ hyaluronic acid (PEGMA/HA) synthesized hydrogel (Fig. 8) was injected in the defected region of femur head using a syringe fitted with a biopsy cannula. This crosslinked gel completely filled up the irregular implantation site and femoral head was reinforced [160]. 6. FUTURE PROSPECTIVE AND CHALLENGES OF TISSUE ENGINEERING The designing of hydrogels by incorporation of cells and bioactive molecules with improved functional properties is gaining attention. There is a strong need to mimic the characteristic properties of ECM, which results in the formation of an ideal environment for cell growth and tissue regeneration. For this, hydrogels are being configured and redesigned by changing their functionalities in view of their different applications. The quest of developing the substitutes of various organs have come up with marvellous clinical application of hydrogel based tissue engineering for various organs such as heart [161-163], skin [164-166], Bone [167, 168], eyes [169, 170], cartilage of human body. However, there are several challenging issues related to this industry for the improvement of the tissue engineered materials. The quality control of the polymeric materials used in the development of artificial implants is a key challenge. The tissue engineering and regenerative medicine International society of Americas (TERMIS-AM) industry committee conducted a survey (2010) [171] on the hurdles associated in various regenerative medicine products. This survey highlighted the various



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Fig. (8). Ex vivo demonstrated that biodegradable injectable PEGMC/HA (45) can be injected into femoral head for reinforcement (A) PEGMC/HA (45) solution loaded in cannula injectoion tool; (B) The cored femoral head with a cylindrical cavity; (C) PEGMC/HA (45) being injected into collapsed femorl head ; and (D) the sectional view of cemented femoral head with CPEGMC/HA (45) composite. Crosslinking was achieved within 5 minutes of injection. Reproduced by permission of The Royal Society of Chemistry from Ref. [160] Gyawali, D.; Nair, P.; Kim, H. K.; Yang, J., Citrate-based biodegradable injectable hydrogel composites for orthopedic applications. Biomater. Sci. 2013, 1(1), 52-64.

goals and applications for different sectors of government and financial industry. It was also found that investors consider muscoskeletal products and their first choice is the products in clinical developmental stage [171]. The progress in the clinical applications of the various polymeric hydrogels by decreasing the present limitations has emerged as the major concern. Another challenge is to see bone-on- demand industry. Bone morphogenetic protein BMF complex is an important component for such bones. It has the ability to form bone extraskeleton at a concentration 1,000-fold lower than the individual constituents. Composite materials, immunomodulatory bioproducts are to be explored for favourable bone regenerations and bone repair [138, 172]. Due to poor implant survival and integration, classical bone tissue engineering has been always challenge. Multiple microscale strategies have been introduced to induce and incorporate vascular networks inside the new engineered bone construct before the implantation for the compatibility with the host tissue [173]. The complex nature of cornea in terms of its high transparency, a specific refractive index, the eight types of collagens and GAGs make corneal tissue engineering a challenging field. The systematic organization of corneal constructs is the most important parameter to be considered for best suited corneal substitute. The immunological responses and reactions obtained in an engineered cell seeded graft are im-

portant aspects to be taken care of. A perfect corneal substitute comprising of all the three primary layers is latest in demand. For this stem cell technology can efficiently provide a healthy cornea substitute. The reconstruction of the corneal tissue in vitro/ in vivo still is a puzzle to be solved by using advanced technologies like advanced stem cell culture [174]. For cardiac tissue engineering, the clinical application of various hydrogel based materials imposes challenges to engineer a cardiac tissue having autologous, phenotypically stable cardiac cell population. The three cell myocytes, fibroblasts and vascular cells are generated inside the tissue like matrix. The size and other dimensional parameters should resemble the native heart for the hydrogel scaffold regenerated. The fibrin gel which is being extensively explored in cardiac tissue engineering has to overcome the property of low mechanical strength, which gives rise to breaking of fibrin gels during the contraction and relaxation of heart [163]. Moreover its degradation rate has to be monitored and the use of chemical like aprotinin has to be seen as it is toxic to the cells. The union of micro patterning techniques with stem cell for cardiogenic differentiation can be of great importance. Utilization of renewable cell sources which have the characteristics for cardiac tissue is also currently needed for regenerative medicine [175]. Important properties crucial for hydrogels are their mechanical strength, conductivity, elas-


ticity and oxygen supply and by virtue of these properties hydrogels are applied to various tissue engineering technologies. Recent research is focussed to study on the various ways the polymers are used for the blood vessel network formation in a particular tissue. This is an important aspect as it supports the nutrient transport to the new tissue formed and allows it to sustain in the surrounding environment [1, 11, 176]. The current hydrogel based tissue engineering has to pay an immense importance to tailor an in vitro cell culture environment that resembles and arrange the meshwork of native ECM [177]. Rapid prototyping (RP) techniques are now being adopted for the advancement in tissue engineering. These RP techniques provide a complete hold on the overall characteristic design and modelling of hydrogel scaffold materials [178]. CONFLICT OF INTEREST

Vashist and Ahmad [13] [14] [15] [16] [17] [18]

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The author(s) confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS

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Arti Vashist appreciates the financial support received from the Council of Scientific and Industrial research (CSIR), New Delhi, India for the Senior Research Fellow-‐ ship for this work.

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Received: September 05, 2014

Revised: October 22, 2014

Accepted: March 9, 2015

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