Hydrogels For Cartilage Tissue Engineering Research Articles

Preparation and evaluation of carboxymethyl chitosan/sodium alginate hydrogel for cartilage tissue engineering

This study aimed to optimize the preparation of carboxymethyl chitosan/sodium alginate (CMCS/OSA) compound hydrogels. This study also aimed to investigate the applicability of the hydrogels in cartilage tissue engi-neering. Three groups of CMCS/OSA composite hydrogels with amino-to-aldehyde ratios of 2∶1, 1∶1 and 1∶2 were prepared. The microstructure, physical properties, and cell biocompatibility of the three groups of CMCS/OSA com-posite hydrogels were evaluated. Samples were subjected to scanning electron microscopy, rheological test, adhesion tension test, swelling rate test, and cell experiments to identify the CMCS/OSA composite hydrogel with the cross-linking degree that can meet the requirements for scaffolds in cartilage tissue engineering. The experimental results showed that the CMCS/OSA hydrogel with a amine-to-aldhyde ratio of 1∶1 had good porosity, suitable gelling time, strong adhesive force, stable swelling rate, and good cellular biocompatibility. The CMCS/OSA compound hydrogel prepared with a 1∶1 ratio of amino and aldehyde groups has potential applications in cartilage tissue engineering.

Influence of hydrogel network microstructures on mesenchymal stem cell chondrogenesis in vitro and in vivo

Hydrogels, which provide three-dimensional (3D) niches for encapsulating bone marrow mesenchymal stem cells (BMSCs), are becoming a promising tissue engineering solution for chondrogenic differentiation of BMSCs. However, it remains a challenge to design a hydrogel material for effective chondrogenesis of BMSCs because of the complexity of cartilage ECM and cell–matrix interactions. Thus far, various studies have shown the physical–chemical cues of hydrogel materials to impact BMSCs chondrogenesis, but the design of the 3D network microstructure of the hydrogel to induce BMSCs chondrogenesis is still far from optimized. In this study, we successfully prepared two types of collagen hydrogels, namely, the fibrous network and porous network, with the same chemical composition and similar mechanical strength but with two distinct network microstructures. The two different network microstructures significantly influenced mass transfer, protein adsorption, degradability, and contraction of the collagen hydrogels. Moreover, the cells presented distinct proliferation and morphology in the two hydrogels, which consequently modulated chondrogenic differentiation of BMSCs derived from rat. Collagen hydrogels with a fibrous network promoted more chondrogenic differentiation of BMSCs without additional growth factors in vitro and subcutaneous implantation in vivo than those with a porous network. Moreover, fibrous network resulted in less ECM calcification than porous network. However, the fibrous network could not prevent hypertrophy of the chondrogenic cells induced by BMSCs. Overall, these results revealed that the 3D network microstructure of a hydrogel was a key design parameter for the chondrogenic differentiation of BMSCs. Statement of SignificanceHydrogels had been used to induce the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in cartilage tissue engineering, but the key design parameters remain unoptimized. This was mainly due to the different material properties including composition, strength, and microstructure, which would interplay with each other and result in difficulties to investigate the effects for one factor. In this study, we fabricated two collagen hydrogels with the same chemical composition and mechanical strength, but two distinct network microstructures. The effects of the two network microstructures on the chondrogenic differentiation of BMSCs were investigated by in vitro and in vivo assays. The results highlight the effects of network microstructures and provide important information about optimizing the design of future hydrogels in cartilage tissue engineering.

Fibrin-Genipin Hydrogel for Cartilage Tissue Engineering in Nasal Reconstruction.

Nasal reconstruction is limited by the availability of autologous cartilage. The aim is to investigate an adhesive biomaterial for tissue engineering of nasal cartilage by evaluating mechanical properties of hydrogels made of fibrin crosslinked with genipin as compared to native tissue. Hydrogels of fibrin, fibrin-genipin, and fibrin-genipin with extracellular matrix (ECM) particles were created and evaluated with mechanical testing to determine compression, tensile, and shear properties. Rabbit nasal septal cartilage was harvested and tested in these modalities for comparison. Transmission electron microscopy characterized hydrogel structure. Fibrin-genipin gels had higher compressive, tensile, and shear moduli compared to fibrin alone or fibrin-genipin with ECM. However, all hydrogel formulations had lower moduli than the rabbit nasal septal cartilage. Electron microscopy showed genipin crosslinking increased structural density of the hydrogel and that cartilage ECM created larger structural features with lower crosslinking density. The addition of genipin significantly improved mechanical properties of fibrin hydrogels by increasing the compressive, tensile, and shear moduli. The addition of cartilage ECM, which can add native structure and composition, resulted in decreased moduli values. Fibrin-genipin is a bioactive and biomechanically stable hydrogel that may offer promise as a scaffold for cartilage tissue engineering in nasal reconstruction, yet further augmentation is required to match material properties of native nasal cartilage.

Structural and mechanical characterization of crosslinked and sterilised nanocellulose-based hydrogels for cartilage tissue engineering

Nanocellulose is a natural biopolymer derived from cellulose. Combined with sodium alginate, it is used to 3D print hydrogels for articular and nasal cartilage engineering and shows good integration, promising cartilage regeneration and mechanical stability over 60 days of implantation in mice. Yet, little is known about their structural and mechanical properties, particularly the impact of crosslinking and sterilisation methods. This study investigates the impact of different calcium chloride crosslinker concentrations and sterilization methods on the structural and mechanical properties of nanocellulose-based hydrogels containing plant-derived cellulose nanofibrils, cellulose nanocrystals or a blend of the two. Crosslinking significantly alters the overall network distribution, surface morphology, pore size and porosity of the hydrogels. Sterilisation has a striking effect on pore size and affects swelling depending on the sterilisation method. The effect of crosslinker and sterilisation on the overall properties of the hydrogels was reliant on the form of nanocellulose that comprised them.

A Novel Biodegradable and Thermosensitive Poly(Ester-Amide) Hydrogel for Cartilage Tissue Engineering.

Thermosensitive hydrogels are attractive alternative scaffolding materials for minimally invasive surgery through a simple injection and in situ gelling. In this study, a novel poly(ester-amide) polymer, methoxy poly(ethylene glycol)-poly(pyrrolidone-co-lactide) (mPDLA, P3L7) diblock copolymer, was synthesized and characterized for cartilage tissue engineering. A series of amphiphilic diblock copolymers was synthesized by ring-opening polymerization of mPEG 550, D,L-lactide, and 2-pyrrolidone. By dynamic light scattering analysis and tube-flipped-upside-down method, viscoelastic properties of the mPDLA diblock copolymer solution exhibited sol-gel transition behavior as a function of temperature. An in vitro degradation assay showed that degradation acidity was effectively reduced by introducing the 2-pyrrolidone monomer into the polyester hydrogel. Besides, mPDLA exhibited great biocompatibility in vitro for cell encapsulation due to a high swelling ratio. Moreover, cell viability and biochemical analysis proved that the mPDLA hydrogel presented a great chondrogenic response. Taken together, these results demonstrate that mPDLA hydrogels are promising injectable scaffolds potentially applicable to cartilage tissue engineering.

In Vitro Screening of Molecularly Engineered Polyethylene Glycol Hydrogels for Cartilage Tissue Engineering using Periosteum-Derived and ATDC5 Cells.

The rapidly growing field of tissue engineering and regenerative medicine has brought about an increase in demand for biomaterials that mimic closely the form and function of biological tissues. Therefore, understanding the cellular response to the changes in material composition moves research one step closer to a successful tissue-engineered product. With this in mind, polyethylene glycol (PEG) hydrogels comprised of different concentrations of polymer (2.5%, 4%, 6.5%, or 8% (w/v)); different protease sensitive, peptide cross-linkers (VPMSMRGG or GPQGIWGQ); and the incorporation or lack of a peptide cell adhesion ligand (RGD) were screened for their ability to support in vitro chondrogenesis. Human periosteum-derived cells (hPDCs), a mesenchymal stem cell (MSC)-like primary cell source, and ATDC5 cells, a murine carcinoma-derived chondrogenic cell line, were encapsulated within the various hydrogels to assess the effects of the different formulations on cellular viability, proliferation, and chondrogenic differentiation while receiving exogenous growth factor stimulation via the medium. Through the results of this screening process, the 6.5% (w/v) PEG constructs, cross-linked with the GPQGIWGQ peptide and containing the RGD cell binding molecule, demonstrated an environment that consistently supported cellular viability and proliferation as well as chondrogenic differentiation.

Injectable hydrogels and nanocomposite hydrogels for cartilage regeneration.

Cartilage loss due to age-related degeneration and mechanical trauma is a significant and challenging problem in the field of surgical medicine. Unfortunately, cartilage tissue can be characterized by the lack of regenerative ability. Limitations of conventional treatment strategies, such as auto-, allo-, and xenografts or implants stimulate an increasing interest in the tissue engineering approach to cartilage repair. This review discusses the application of polymer-based scaffolds, with an emphasis on hydrogels in cartilage tissue engineering. We highlight injectable hydrogels with various micro- and nanoparticles, as they constitute a novel and attractive type of scaffolds. We discuss advantages, limitations, and future perspectives of injectable nanocomposite hydrogels for cartilage tissue regeneration. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2762-2776, 2018.

Application of Hydrogels in Cartilage Tissue Engineering.

Cartilage has limited ability for self-repairing, prompting the search for cartilage substitutes that can repair cartilage defects. Hydrogels have attracted attention as cartilage substitutes, since their mechanical properties, swelling ability and lubricating behavior are similar to extracellular matrix of articular cartilage. Hydrogels can be of natural, synthetic or hybrid origin, and hydrogels can encapsulate stem cells and/or be loaded with growth factors to promote cell differentiation into a chondrogenic phenotype. This review summarizes basic research advances in using hydrogels to repair cartilage defects. The raw materials, stem cells and growth factors used to prepare hydrogels are discussed. Substantial success has been achieved in small animal models of cartilage repair and regeneration, but further research is needed to improve hydrogels' mechanical properties and their integration with surrounding tissues.

Component effect of stem cell-loaded thermosensitive polypeptide hydrogels on cartilage repair

Biophysical properties of the desired biomimetic scaffolds, such as porosity and elasticity, have been proven associated with the efficacy of cartilage regeneration. In this work, the copolymers of poly(l-alanine)-block-poly(ethylene glycol)-block-poly(l-alanine) (PA-PEG-PA) and poly(l-alanine-co-l-phenylalanine)-block-poly(ethylene glycol)-block-poly(l-alanine-co-l-phenylalanine) (PAF-PEG-PAF) with different ratios of alanine to phenylalanine were synthesized. The introduction of a hydrophobic amino acid, i.e., phenylalanine, into polyalanine-based thermosensitive hydrogel led to the enhanced gelation behaviors and upregulated mechanical properties. Moreover, the increase of phenylalanine content resulted in the enlarged pore size and enhanced mechanical strength of PAF-PEG-PAF thermogel, followed by the regeneration of hyaline-like cartilage with reduced fibrous tissue formation in vivo. The findings indicated the great potential of thermosensitive polypeptide hydrogels in cartilage tissue engineering. Statement of SignificanceArticular cartilage defect has limited self-repair ability due to the lack of blood supply and innervation, which may lead to knee osteoarthritis afterwards. Injectable hydrogels are demonstrated possessing outstanding properties as biomimetic scaffolds in cartilage tissue engineering, while the effect of biophysical properties on the efficacy of cartilage regeneration has not been revealed. Herein, the poly(ethylene glycol)-polypeptide triblock copolymers with different ratios of alanine to phenylalanine were synthesized. The sol-to-gel transition temperature and the critical gelation concentration decreased as the increased amount of phenylalanine unit, resulting in the enlarged pore size and enhanced mechanical strength. These features lead to better regeneration of hyaline-like cartilage with reduced fibrous tissue formation, indicating great potential of thermosensitive polypeptide hydrogels for efficient cartilage repair.

Correction: An injectable hyaluronic acid/PEG hydrogel for cartilage tissue engineering formed by integrating enzymatic crosslinking and Diels–Alder “click chemistry”

Correction for ‘An injectable hyaluronic acid/PEG hydrogel for cartilage tissue engineering formed by integrating enzymatic crosslinking and Diels–Alder “click chemistry”’ by Feng Yu et al., Polym. Chem., 2014, 5, 1082–1090.

Role of dexamethasone in the long-term functional maturation of MSC-laden hyaluronic acid hydrogels for cartilage tissue engineering.

The purpose of study was to investigate the maturation of mesenchymal stem cells (MSC) laden in HA constructs with various combinations of chemically defined medium (CM) components and determine the impact of dexamethasone and serum on construct properties. Constructs were cultured in CM with the addition or withdrawal of media components or were transferred to serum containing media that partially represents an in vivo-like condition where pro-inflammatory signals are present. Constructs cultured in CM+ (CM with TGF-β3) and DEX- (CM+ without dexamethasone) conditions produced robust matrix, while those in ITS/BSA/LA- (CM+ without ITS/BSA/LA) and Serum+ (10% FBS with TGF-β3) produced little matrix. While construct properties in DEX- were greater than those in CM+ at 4 weeks, properties in CM+ and DEX- reversed by 8 weeks. While construct properties in DEX- were greater than those in CM+ at 4 weeks, the continued absence or removal of dexamethasone resulted in marked GAG loss by 8 weeks. Conversely, the continued presence or new addition of dexamethasone at 4 weeks further improved or maintained construct properties through 8 weeks. Finally, when constructs were converted to Serum (in the continued presence of TGF-β3 with or without dexamethasone) after pre-culture in CM+ for 4 weeks, GAG loss was attenuated with addition of dexamethasone. Interestingly, however, collagen content and type was not impacted. In conclusion, dexamethasone influences the functional maturation of MSC-laden HA constructs, and may help to maintain properties during long-term culture or with in vivo translation by repressing pro-inflammatory signals. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1717-1727, 2018.

Self-crosslinking and injectable chondroitin sulfate/pullulan hydrogel for cartilage tissue engineering

Injectable hydrogels derived from natural polysaccharides have great application prospects in cartilage tissue engineering (CTE). In this study, chondroitin sulfate was functionalized with adipic dihydrazide (CS-ADH), and pullulan was oxidized (oxPL). We fabricated a self-crosslink, biodegradable, in situ forming, injectable hydrogel by covalent hydrazone crosslinking of polysaccharides, without using extra cross-linking agents and releasing harmful byproducts under physiological conditions. The gelation time, equilibrium swelling, degradation behavior, network morphology and mechanical properties of CS-ADH/oxPL hydrogels were well manipulated by varying the weight ratio and concentration of CS-ADH and oxPL. In addition, encapsulation of rabbit articular chondrocytes in CS-ADH/oxPL hydrogels was observed after 14 days culture. Live/Dead staining assay demonstrated that the hydrogel system possessed good cytocompatibility. Sulfated glycosaminoglycan (sGAG) contents indicated that the hydrogel system favored cartilaginous extracellular matrix (ECM) deposition. Furthermore, the hydrogel system could maintain the chondrocyte phenotype and enhance chondrogenesis, which was evaluated in terms of their protein and gene expression. These features support that CS-ADH/oxPL hydrogels have a potential as an injectable cell delivery carrier scaffold in CTE.

Laponite nanoparticle-associated silated hydroxypropylmethyl cellulose as an injectable reinforced interpenetrating network hydrogel for cartilage tissue engineering.

Articular cartilage is a tissue that fails to heal spontaneously. To address this clinically relevant issue, biomaterial-assisted cell therapy is considered promising but often lacks adequate mechanical properties. Our objective was to develop a composite hydrogel using a small amount of nano reinforcement (laponite) capable of gelling within polysaccharide based self-crosslinking hydrogel. This new hybrid construct demonstrates an interpenetrating network (IPN) which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, O2 diffusion and the ability of chondrogenic cells to self-organize in cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects and will now be considered in a large animal model of articular cartilage defects.

Fabrication of Highly Crosslinked Gelatin Hydrogel and Its Influence on Chondrocyte Proliferation and Phenotype.

Gelatin methacrylate (GelMA) hydrogels have been widely studied for biomedical applications, such as tissue engineering and drug delivery, because of their good biocompatibility and injectability. However, the quick degradation and low mechanical property of GelMA hydrogels need to be improved for further applications, especially for long-term implantation. In this study, a sequential double modification of gelatin was used to achieve high density of photocrosslinkable double bonds in gelatin derivatives. The amino groups in gelatin were first reacted with methacrylic anhydride. After this, the hydroxyl and carboxyl groups in gelatin were reacted with glycidyl methacrylate to obtain the double modified gelatin macromer. The double modified gelatin macromer was used to prepare gelatin hydrogels with high crosslinking density. The hydrogels exhibited high storage modulus and low degradation. Culture of bovine articular chondrocytes in the gelatin hydrogels showed that chondrocytes had round morphology and maintained a cartilaginous phenotype while cell proliferation was hampered. This method for increasing crosslinking density should be useful for preparation of stable hydrogels for cartilage tissue engineering.

Preparation and properties of polyvinyl alcohol (PVA) and hydroxylapatite (HA) hydrogels for cartilage tissue engineering.

A novel bioactive hydrogel for cartilage tissue based on polyvinyl alcohol (PVA) and hydroxylapatite (HA) were prepared, the effects of its component contents on the mechanical properties and microstructure of the hydrogel were investigated. The important properties of the scaffold composites, such as density, porosity, compressive modulus and microstructure were studied and analyzed through various measurements and methods. The biodegradability of hydrogel was evaluated by soaking the samples into artificial degradation solution at body temperature (36 - 37 oC) in vitro. Experimental results showed that the PVA/HA hydrogels had a density of 0.572 - 0.683 g/cm3, a porosity of 63.25 - 96.14% and a compressive modulus of 5.62 - 8.24 MP. The HA compound in the hydrogels enhanced the biodegradation significantly and linearly increased the rate of biodegradation by 2.3 - 8.5 %. The compressive modulus of PVA/HA exhibited a linear reduce to 0.86 - 1.53 MP with the time of degradation. The scaffold composites PVA/HA possess a high porosity, decent compressive modulus and good biodegradability. After further optimizing the structure and properties, this composite might be considered as novel hydrogel biomaterials to be applied in the field of cartilage tissue engineering.

Self-crosslinking and injectable hyaluronic acid/RGD-functionalized pectin hydrogel for cartilage tissue engineering

In the present study, we developed a biomimetic injectable hydrogel system based on hyaluronic acid-adipic dihydrazide and the oligopeptide G4RGDS-grafted oxidized pectin, in which their hydrazide and aldehyde-derivatives enable covalent hydrazone crosslinking of polysaccharides. The hydrazone crosslinking strategy is simple, while circumventing toxicity, making this injectable system feasible, minimally invasive and easily translatable for regenerative purposes. By varying their weight ratios, the physicochemical properties of the mechanically stable hydrogel system were easily adjustable. Additionally, the preliminary studies demonstrated that chondrocyte behavior was dependent on HA/pectin composition and the presence of integrin binding moieties. Specifically, the incorporation of a certain amount of G4RGDS oligopeptide into HA/pectin-based hydrogels could serve as a biologically active microenvironment that supported chondrocyte phenotype and facilitated chondrogenesis. Furthermore, the hydrogel system exhibited acceptable tissue compatibility by using a mouse subcutaneous implantation model. Overall, the novel injectable multicomponent hydrogel presented here is expected to be useful biomaterial scaffold for cartilage tissue regeneration.

Recent advances in hydrogels for cartilage tissue engineering.

Articular cartilage is a load-bearing tissue that lines the surface of bones in diarthrodial joints. Unfortunately, this avascular tissue has a limited capacity for intrinsic repair. Treatment options for articular cartilage defects include microfracture and arthroplasty; however, these strategies fail to generate tissue that adequately restores damaged cartilage. Limitations of current treatments for cartilage defects have prompted the field of cartilage tissue engineering, which seeks to integrate engineering and biological principles to promote the growth of new cartilage to replace damaged tissue. To date, a wide range of scaffolds and cell sources have emerged with a focus on recapitulating the microenvironments present during development or in adult tissue, in order to induce the formation of cartilaginous constructs with biochemical and mechanical properties of native tissue. Hydrogels have emerged as a promising scaffold due to the wide range of possible properties and the ability to entrap cells within the material. Towards improving cartilage repair, hydrogel design has advanced in recent years to improve their utility. Some of these advances include the development of improved network crosslinking (e.g. double-networks), new techniques to process hydrogels (e.g. 3D printing) and better incorporation of biological signals (e.g. controlled release). This review summarises these innovative approaches to engineer hydrogels towards cartilage repair, with an eye towards eventual clinical translation.

Fabrication of injectable high strength hydrogel based on 4-arm star PEG for cartilage tissue engineering.

Hydrogels prepared from poly(ethylene glycol) (PEG) are widely applied in tissue engineering, especially those derived from a combination of functional multi-arm star PEG and linear crosslinker, with an expectation to form a structurally ideal network. However, the poor mechanical strength still renders their further applications. Here we examined the relationship between the dynamics of the pre-gel solution and the mechanical property of the resultant hydrogel in a system consisting of 4-arm star PEG functionalized with vinyl sulfone and short dithiol crosslinker. A method to prepare mechanically strong hydrogel for cartilage tissue engineering is proposed. It is found that when gelation takes place at the overlap concentration, at which a slow relaxation mode just appears in dynamic light scattering (DLS), the resultant hydrogel has a local maximum compressive strength ∼20MPa, while still keeps ultralow mass concentration and Young's modulus. Chondrocyte-laden hydrogel constructed under this condition was transplanted into the subcutaneous pocket and an osteochondral defect model in SCID mice. The invivo results show that chondrocytes can proliferate and maintain their phenotypes in the hydrogel, with the production of abundant extracellular matrix (ECM) components, formation of typical chondrocyte lacunae structure and increase in Young's modulus over 12 weeks, as indicated by histological, immunohistochemistry, gene expression analyses and mechanical test. Moreover, newly formed hyaline cartilage was observed to be integrated with the host articular cartilage tissue in the defects injected with chondrocytes/hydrogel constructs. The results suggest that this hydrogel is a promising candidate scaffold for cartilage tissue engineering.

Injectable dextran hydrogels fabricated by metal-free click chemistry for cartilage tissue engineering

Injectable dextran-based hydrogels were prepared for the first time by bioorthogonal click chemistry for cartilage tissue engineering. Click-crosslinked injectable hydrogels based on cyto-compatible dextran (Mw=10kDa) were successfully fabricated under physiological conditions by metal-free alkyne-azide cycloaddition (click) reaction between azadibenzocyclooctyne-modified dextran (Dex-ADIBO) and azide-modified dextran (Dex-N3). Gelation time of these dextran hydrogels could be regulated in the range of approximately 1.1 to 10.2min, depending on the polymer concentrations (5% or 10%) and ADIBO substitution degree (DS, 5 or 10) of Dex-ADIBO. Rheological analysis indicated that the dextran hydrogels were elastic and had storage moduli from 2.1 to 6.0kPa with increasing DS of ADIBO from 5 to 10. The in vitro tests revealed that the dextran hydrogel crosslinked from Dex-ADIBO DS 10 and Dex-N3 DS 10 at a polymer concentration of 10% could support high viability of individual rabbit chondrocytes and the chondrocyte spheroids encapsulated in the hydrogel over 21days. Individual chondrocytes and chondrocyte spheroids in the hydrogel could produce cartilage matrices such as collagen and glycosaminoglycans. However, the chondrocyte spheroids produced a higher content of matrices than individual chondrocytes. This study indicates that metal-free click chemistry is effective to produce injectable dextran hydrogels for cartilage tissue engineering.

Smart Polymeric Hydrogels for Cartilage Tissue Engineering: A Review on the Chemistry and Biological Functions.

Stimuli responsive hydrogels (SRHs) are attractive bioscaffolds for tissue engineering. The structural similarity of SRHs to the extracellular matrix (ECM) of many tissues offers great advantages for a minimally invasive tissue repair. Among various potential applications of SRHs, cartilage regeneration has attracted significant attention. The repair of cartilage damage is challenging in orthopedics owing to its low repair capacity. Recent advances include development of injectable hydrogels to minimize invasive surgery with nanostructured features and rapid stimuli-responsive characteristics. Nanostructured SRHs with more structural similarity to natural ECM up-regulate cell-material interactions for faster tissue repair and more controlled stimuli-response to environmental changes. This review highlights most recent advances in the development of nanostructured or smart hydrogels for cartilage tissue engineering. Different types of stimuli-responsive hydrogels are introduced and their fabrication processes through physicochemical procedures are reported. The applications and characteristics of natural and synthetic polymers used in SRHs are also reviewed with an outline on clinical considerations and challenges.