Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications

Injectable hydrogels with biodegradability have in situ formability which in vitro/in vivo allows an effective and homogeneous encapsulation of drugs/cells, and convenient in vivo surgical operation in a minimally invasive way, causing smaller scar size and less pain for patients. Therefore, they have found a variety of biomedical applications, such as drug delivery, cell encapsulation, and tissue engineering. This critical review systematically summarizes the recent progresses on biodegradable and injectable hydrogels fabricated from natural polymers (chitosan, hyaluronic acid, alginates, gelatin, heparin, chondroitin sulfate, etc.) and biodegradable synthetic polymers (polypeptides, polyesters, polyphosphazenes, etc.). The review includes the novel naturally based hydrogels with high potential for biomedical applications developed in the past five years which integrate the excellent biocompatibility of natural polymers/synthetic polypeptides with structural controllability via chemical modification. The gelation and biodegradation which are two key factors to affect the cell fate or drug delivery are highlighted. A brief outlook on the future of injectable and biodegradable hydrogels is also presented (326 references).     

Injectable hydrogels

Hydrogels are promising for a variety of medical applications due to their high water content and mechanical similarity to natural tissues. When made injectable, hydrogels can reduce the invasiveness of application, which in turn reduces surgical and recovery costs. Key schemes used to make hydrogels injectable include in situ formation due to physical and/or chemical cross‐linking. Advances in polymer science have provided new injectable hydrogels for applications in drug delivery and tissue engineering. A number of these injectable hydrogel systems have reached the clinic and impact the health care of many patients. However, a significant remaining challenge is translating the ever‐growing family of injectable hydrogels developed in laboratories around the world to the clinic. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012     

Plasmid DNA hydrogels for biomedical applications

In the last few years, our research group has focused on the design and development of plasmid DNA (pDNA) based systems as devices to be used therapeutically in the biomedical field. Biocompatible macro and micro plasmid DNA gels were prepared by a cross-linking reaction. For the first time, the pDNA gels have been investigated with respect to their swelling in aqueous solution containing different additives. Furthermore, we clarified the fundamental and basic aspects of the solute release mechanism from pDNA hydrogels and the significance of this information is enormous as a basic tool for the formulation of pDNA carriers for drug/gene delivery applications. The co-delivery of a specific gene and anticancer drugs, combining chemical and gene therapies in the treatment of cancer was the main challenge of our research. Significant progresses have been made with a new p53 encoding pDNA microgel that is suitable for the loading and release of pDNA and doxorubicin. This represents a strong valuable finding in the strategic development of systems to improve cancer cure through the synergetic effect of chemical and gene therapy.     

Photosensitive peptide hydrogels as smart materials for applications

Photosensitive supramolecular peptide hydrogels with the gelators forming by the integration of photosensitive moieties and peptides have been briefly summarized the hydrogelation capabilities, the expressing manner serving as smart materials, and practical applications.     

Temperature-responsive compounds as in situ gelling biomedical materials

Aqueous solutions that undergo sol-to-gel transition as the temperature increases have been extensively studied during the last decade. The material can be designed by controlling the hydrophilic and hydrophobic balance of the material. Basically, the molecular weight of the hydrophilic block and hydrophobic block of a compound should be fine-tuned from the synthetic point of view. In addition, stereochemistry, microsequence, topology, and nanostructures of the compound also affect the transition temperature, gel window, phase diagram, and modulus of the gel. From a practical point of view, biodegradability, biocompatibility, and interactions between the material and drug or cell should be considered in designing a thermogelling material. The interactions are particularly important in that they control drug release profile and initial burst release of the drug in the drug delivery system, and affect cell proliferation, differentiation, and biomarker expression in three-dimensional cell culture and tissue engineering application. This review provides an in-depth summary of the recent progress of thermogelling systems including polymers, low molecular compounds, and nanoemulsions. Their biomedical applications were also comparatively discussed. In addition, perspectives on future material design of a new thermogelling material and its application are suggested.     

Three-dimensional porous HPMA-co-DMAEM hydrogels for biomedical application

The aim of this work is to develop a novel biocompatible drug delivery carrier and tissue engineering scaffold with the ability of controlled drug release and also tissue regeneration. We have synthesized N-(2-hydroxypropyl)methacrylamide and 2-(dimethylamino)ethyl methacrylate copolymer-based hydrogels loaded with doxorubicin and tested in vitro. The manifestation of temperature sensitivity is noted with a sharp decrease or increase in hydrogel optical transparency that happens with the temperature exceeding a critical transition value. The drug release profile exhibited pH-sensitive behavior of the hydrogel. The hydrolytic degradation of gel and in vitro studies of polymer–doxorubicin conjugate and doxorubicin release from hydrogel matrix indicated that hydrogels were stable under acidic conditions (in buffers at pH 4.64 and 6.65). In both drug forms, polymer–doxorubicin conjugate and free doxorubicin could be released from the hydrogel scaffold at a rate depending directly on either the rate of drug diffusion from the hydrogel or rate of hydrogel degradation or at rate controlled by a combination of the both processes. In vitro analysis showed homogenous cell attachment and proliferation on synthesized hydrogel matrix. In vivo implantation demonstrated integration of the gel with the surrounding tissue of mice within 2 weeks and prominent neo-angiogenesis observed in the following weeks. This multifunctional hydrogels can easily overcome biological hurdles in the in vivo conditions where the pH range changes drastically and could attain higher site-specific drug delivery improving the efficacy of the treatment in various therapeutical applications, especially in cancer therapy, and could also be used as tissue engineering scaffold due to its porous interconnected and biocompatible behavior.     

Photocrosslinkable chitosan hydrogels and their biomedical applications

Chitosan is a bioactive macromolecule with a wide variety of applications due to its excellent biological properties such as biodegradability, biocompatibility, and antibacterial activity, and so forth. This highlight focuses on the preparation of photoactive chitosans, the formation of photocrosslinkable chitosan hydrogels, and the related photopolymerization mechanisms. Moreover, the great potential applications of photocrosslinkable chitosan hydrogels for human tissues are also discussed. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1862–1871     

Advances in nitric oxide-releasing hydrogels for biomedical applications

Hydrogels provide a plethora of advantages to biomedical treatments due to their highly hydrophilic nature and tissue-like mechanical properties. Additionally, the numerous and widespread endogenous roles of nitric oxide have led to an eruption in research developing biomimetic solutions to the many challenges the biomedical world faces. Though many design factors and fabrication details must be considered, utilizing hydrogels as nitric oxide delivery vehicles provides promising materials in several applications. Such applications include cardiovascular therapy, vasodilation and angiogenesis, antimicrobial treatments, wound dressings, and stem cell research. Herein, a recent update on the progress of NO-releasing hydrogels is presented in depth. In addition, considerations for the design and fabrication of hydrogels and specific biomedical applications of nitric oxide-releasing hydrogels are discussed.     

Injectable and self-healing hydrogels with tissue adhesiveness and antibacterial activity as wound dressings for infected wound healing

The design of wound dressings with excellent self-healing ability, adequate adhesion, good biocompatibility, and potential antibacterial ability is of great significance for the healing of infected wounds arising from human activities. Herein, a series of multi-functional hydrogel dressings, poly(ionized isocyanoethyl methacrylate-glutamine)/poly(hexamethylene guanidine) (iG_x/PHMG_y) hydrogels, were obtained through homopolymerization of fully ionized isocyanoethyl methacrylate-glutamine (iIEM-Gln) in the presence of poly(hexamethylene guanidine) (PHMG), in which strong hydrogen bonds were formed among urea groups in the P (iIEM-Gln) chain to form a stable hydrogel network. The prepared iG_x/PHMG_y hydrogels exhibited adequate self-healing ability and tissue adhesion, which could be firmly adhered to the wound surface and remained intact during application. In addition, the presence of PHMG imparted good antibacterial activity to the hydrogels for the effective promotion of the wound healing in S. aureus infected skin wound on mice. Overall, this multi-functional hydrogel provides a facile and effective strategy for the design of infected wound dressings, and may show great potential in clinical applications.     

Injectable poly(ethylene glycol) hydrogels for sustained doxorubicin release

Water‐soluble poly(ethylene glycol) derivatives with multiple “clickable” mercapto groups or double bonds were facilely synthesized in a large scale by direct polycondensation of oligo(ethylene glycol) diol with mercaptosuccinic acid or maleic acid catalyzed by scandium trifluoromethanesulfonate under mild conditions. Injectable hydrogels containing doxorubicin hydrochloride (DOX · HCl) could be rapidly formed using these poly(ethylene glycol) derivatives as precursors via in situ thiol‐ene “click” reaction under physiological conditions without light, initiator, or metal catalyst. DOX · HCl could be sustained released from the hydrogels as a result of the hindrance of the three dimensional hydrogel network on the drug molecules, which makes this kind of DOX‐loaded hydrogels a promising candidate for localized tumor chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.     

Polymeric gels and hydrogels for biomedical and pharmaceutical applications

Hydrogels are formed when a three‐dimensional polymeric network is loosely crosslinked. They are swollen by water but not dissolved in it. Hydrogels may display reversible sol–gel transitions, induced by changes in the environmental conditions such as temperature, pH, ionic strength, phase separation, wave length of light, crystallinity, etc. Hydrogel is described as smart or intelligent when sharp transition is induced by small change in such conditions. For the shape‐memory hydrogels, reversible change in shape may also be induced by such stimuli. The preparation and applications of the molecularly imprinted polymeric hydrogels (MIPs) are illustrated by a few examples. The use of shape sensitive hydrogels in microfluidic is mentioned. Application of hydrogels for chronobiology and chronotherapy is outlined. The conversion of hydrogels into aerogels and their respective properties is discussed. Copyright © 2009 John Wiley & Sons, Ltd.     

Injectable solid peptide hydrogel as a cell carrier: effects of shear flow on hydrogels and cell payload

β-hairpin peptide-based hydrogels are a class of injectable solid hydrogels that can deliver encapsulated cells or molecular therapies to a target site via syringe or catheter injection as a carrier material. These physical hydrogels can shear-thin and consequently flow as a low-viscosity material under a sufficient shear stress but immediately recover back into a solid upon removal of the stress, allowing them to be injected as preformed gel solids. Hydrogel behavior during flow was studied in a cylindrical capillary geometry that mimicked the actual situation of injection through a syringe needle in order to quantify effects of shear-thin injection delivery on hydrogel flow behavior and encapsulated cell payloads. It was observed that all β-hairpin peptide hydrogels investigated displayed a promising flow profile for injectable cell delivery: a central wide plug flow region where gel material and cell payloads experienced little or no shear rate, and a narrow shear zone close to the capillary wall where gel and cells were subject to shear deformation. The width of the plug flow region was found to be weakly dependent on hydrogel rigidity and flow rate. Live-dead assays were performed on encapsulated MG63 cells 3 h after injection flow and revealed that shear-thin delivery through the capillary had little impact on cell viability and the spatial distribution of encapsulated cell payloads. These observations help us to fundamentally understand how the gels flow during injection through a thin catheter and how they immediately restore mechanically and morphologically relative to preflow, static gels.     

The design,mechanism and biomedical application of self-healing hydrogels

Current advances made in self-healing hydrogels relating to the design strategies, self-healing mechanism, testing methods and biomedical application in vivo were extensively reviewed in this article.     

DNA-based supramolecular hydrogels: From construction strategies to biomedical applications

DNA-based supramolecular hydrogels are important and promising biomaterials for various applications due to their inherent biocompatibility and tunable physicochemical properties. The three-dimensional supramolecular matrix of DNA formed by non-covalently dynamic cross-linking provides exceptional adaptability, self-healing, injectable and responsive properties for hydrogels. In addition, DNA hydrogels are also ideal bio-scaffold materials owing to their tissue-like mechanics and intrinsic biological functions. Technically, DNA can assemble into supramolecular networks by pure complementary base pairing; it can also be combined with other building blocks to construct hybrid hydrogels. This review focuses on the development and construction strategies of DNA hydrogels. Assembly and synthesis methods, diverse responsiveness and biomedical applications are summarized. Finally, the challenges and prospects of DNA-based supramolecular hydrogels are discussed.     

Multifunctional polymeric materials for biomedical applications

The work performed by our research group during the last few years in the area of bioerodible-biodegradable polymers as designed to the formulation of systems for the controlled delivery of drugs and as specific sorbents of uraemic toxins is broadly reviewed. In particular, attention has been focused on the strategies adopted in the preparation of functional polymers containing hydroxyl or carboxyl groups, suitable to establish specific bonding and non-bonding interactions with conventional and proteic drugs.     

Thermosensitive Chitosans as Novel Injectable Biomaterials

Two kinds of water soluble thermosensitive chitosan copolymers were prepared by graft polymerization of N-isopropylacrylamide (NIPAAm) onto chitosan using cerium ammonium nitrate (CAN) as an initiator (chitosan-g-NIPAAm) and by coupling monocarboxy Pluronic^® with chitosan using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and N-hydroxysuccin-imide (NHS) as coupling agents (chitosan-Pluronic^®). The physicochemical properties of the resulting copolymers were characterized and they formed thermally reversible hydrogel, which exhibits a lower critical solution temperature (LCST) at 34°C in aqueous solutions. The human mesenchymal stem cells (hMSCs) were cultured in the chiotsan-g-NIPAAm in vitro. Chondrogenic differentiation was induced in the chitosan-g-NIPAAm gel. Therefore, chondrogenic differentiated cells from MSCs with a thermo-sensitive chitosan-g-NIPAAm could be used as an injectable cell-polymer complex. In summary, chitosan-g-NIPAAm and chitosan-Pluronic^® attest to their usefulness as injectable materials because of their thermally reversible property and relatively good biocompatibility.     

Injectable biodegradable hydrogels composed of hyaluronic acid-tyramine conjugates for drug delivery and tissue engineering

The sequential injection of hyaluronic acid-tyramine conjugates and enzymes forms biodegradable hydrogels in vivo by enzyme-induced oxidative coupling, offering high potential as a promising biomaterial for drug delivery and tissue engineering.     

Injectable hydrogels for targeted delivering of therapeutic molecules for tissue engineering and disease treatment

Hydrogels are cross‐linked three‐dimensional polymeric networks that play a vital role in solving the pharmacological and clinical limitations of the existing systems due to their unique physical properties such as affinity for biological fluids, tunable porous nature, high water content, ease of preparation, flexibility, and biocompatibility. Hydrogel also mimics the living natural tissue, which opens several opportunities for its use in biomedical areas. Injectable hydrogel allows temporal control and exceptional spatial arrangements and can offset hitches with established hydrogel‐based drug delivery systems. Here, we review the recent development of injectable hydrogels and their significance in the delivery of therapeutics such as cells, genes, and drug molecules and how these innovatory systems can complement the current delivery systems.