Strengthening injectable thermo-sensitive NIPAAm-g-chitosan hydrogels using chemical cross-linking of disulfide bonds as scaffolds for tissue engineering

Lai J., Luo L.

This study reports, for the first time, the development of a chitosan-g-poly(N-isopropylacrylamide) (Chi-PN) biodegradable in situ gelling delivery system for ocular pilocarpine administration through intracameral injection. The number of thermo-responsive polymer segments grafted onto the chitosan via carbodiimide-mediated formation of amide linkages was greatly affected by varying the feeding amount of carboxyl-terminated poly(N-isopropylacrylamide) in the synthesis, thereby determining the phase transition temperature and enzymatic degradability of Chi-PN materials. The increase in grafting ratio facilitated temperature triggered gelation and drug encapsulation at physiological conditions. Additionally, the slow biodegradation process of delivery carriers was responsible for the delayed pilocarpine release, which allowed that the drug concentration could reach minimum therapeutic level for treating glaucoma during 42days of the study. All of the synthesized Chi-PN carriers demonstrated good ocular biocompatibility with lens epithelial cell cultures. In a rabbit model of experimental glaucoma, the intraocular pressure-lowering and miotic as well as corneal endothelial preservation responses to pilocarpine strongly depended on the drug release profiles. It is concluded that injectable biodegradable chitosan-based thermogels can be potentially utilized as intracameral biomaterials for extended release of antiglaucoma medications and improved performance of delivery carriers.

Patil A.S., Gadad A.P., Hiremath R.D., Dandagi P.M.

The objective of the present study was to synthesize and evaluate the effect of change in concentration of chitosan (CS) and N,N-methylenebisacrylamide (MBA)- a cross linking agent, on various properties such as lower critical solution temperature (LCST), zeta potential, particle size and poly dispersity index (PDI) of the synthesized co-polymer. Nine different formulations of chitosan-g-poly (N-isopropylacrylamide) (CS-g-PNIPAAm) co-polymer with varying CS and MBA concentrations were synthesized by a surfactant free dispersion copolymerization method. The synthesized co-polymer was further characterized and confirmed for its structure, morphology, particle size, zeta-potential, thermo and pH responsive properties, in-vitro cyto-compatability and stability studies using various analytical tools. The data confirms the successful synthesis of co-polymer. The increase in the concentrations of CS and MBA during the polymerization of co-polymer, resulted in proportional increase of LCST and zeta potential with decrease in particle size of co-polymeric nanoparticles. pH responsive studies showed that as the pH of the medium increases particle size and zeta potential decreases with increase in LCST of co-polymeric nanoparticles. From the results, it can be inferred that the synthesized co-polymeric nanoparticles exerted thermo and pH responsive properties with biocompatibility. By varying the CS and MBA concentrations in the co-polymer, desired LCST, particle size and zeta potential for co-polymeric nanoparticles can be obtained and thus the synthesized co-polymer may have great potential to be used as a drug carrier (nanoform) with both thermo and pH responsiveness.

Brassinne J., Fustin C., Gohy J.

An orthogonal control over network formation and dynamics is achieved in metallo-supramolecular micellar gels via multi-responsive double hydrophilic copolymers.

Haq M.A., Su Y., Wang D.

Materials which adjust their properties in response to environmental factors such as temperature, pH and ionic strength are rapidly evolving and known as smart materials. Hydrogels formed by smart polymers have various applications. Among the smart polymers, thermoresponsive polymer poly(N-isopropylacrylamide)(PNIPAM) is very important because of its well defined structure and property specially its temperature response is closed to human body and can be finetuned as well. Mechanical properties are critical for the performance of stimuli responsive hydrogels in diverse applications. However, native PNIPAM hydrogels are very fragile and hardly useful for any practical purpose. Intense researches have been done in recent decade to enhance the mechanical features of PNIPAM hydrogel. In this review, several strategies including interpenetrating polymer network (IPN), double network (DN), nanocomposite (NC) and slide ring (SR) hydrogels are discussed in the context of PNIPAM hydrogel.

Wu J., Liu J., Shi Y., Wan Y.

Silk fibroin (SF) and hydroxyapatite (HA) were incorporated into chitosan/glycerophosphate (GP) system to prepare new types of hydrogels. The formulated chitosan/SF/GP and chitosan/SF/HA/GP solutions were found to be injectable at room temperature, and able to form into hydrogels at near-physiological temperature and pH. Rheological measurements showed that elastic modulus of certain chitosan/SF/GP and chitosan/SF/HA/GP gels could reach around 1.8 and 15kPa, respectively, and was much higher than their respective viscous modulus. Compressive measurements revealed that some chitosan/SF/GP and chitosan/SF/HA/GP gels had 8 and 20-fold modulus and strength higher than the chitosan/GP gel, respectively, confirming that compressive properties of these gels were greatly improved. Results obtained from in vivo degradation demonstrated that degradation endurance of the optimized chitosan/SF/GP and chitosan/SF/HA/GP gels was significantly enhanced as compared to the chitosan/GP gel, and the degradation rate of the gels could be regulated by the SF component alone or by the combination of SF and HA components.

Mellati A., Kiamahalleh M.V., Madani S.H., Dai S., Bi J., Jin B., Zhang H.

Providing a controllable and definable three-dimensional (3D) microenvironment for chondrogenic differentiation of mesenchymal stem cells (MSCs) remains a great challenge for cartilage tissue engineering. In this work, poly(N-isopropylacrylamide) (PNIPAAm) polymers with the degrees of polymerization of 100 and 400 (NI100 and NI400) were prepared and the polymer solutions were introduced into the preprepared chitosan porous scaffolds (CS) to form hybrids (CSNI100 and CSNI400, respectively). SEM images indicated that the PNIPAAm gel partially occupied chitosan pores while the interconnected porous structure of chitosan was preserved. MSCs were incorporated within the hybrid and cell proliferation and chondrogenic differentiation were monitored. After 7-day incubation of the cell-laden constructs in a growth medium, the cell viability in CSNI100 and CSNI400 were 54 and 108% higher than that in CS alone, respectively. Glycosaminoglycan and total collagen contents increased 2.6- and 2.5-fold after 28-day culture of cell-laden CSNI400 in the chondrogenic medium. These results suggest that the hybrid structure composed of the chitosan porous scaffold and the well-defined PNIPAAm hydrogel, in particular CSNI400, is suitable for 3D stem cell culture and cartilage tissue engineering. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2764-2774, 2016.

Nieto-Suárez M., López-Quintela M.A., Lazzari M.

Chitosan and gelatin are biodegradable and biocompatible polymers which may be used in the preparation of 3D scaffolds with applications in biomedicine. Chitosan/gelatin scaffolds crosslinked with glutaraldehyde were prepared by ice segregation induced self-assembly (ISISA); a unidirectional freezing at -196°C followed freeze-drying to produce macroporous materials with a well-patterned structure. This process may be included within the green chemistry by the preparation of the porous structures without using organic solvents, moreover is a versatile, non-difficult and cheap process. The scaffolds prepared by ISISA were characterized by scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, thermal gravimetric analysis, differential scanning calorimetry, and their stability was evaluated by degree swelling and degradation tests. The scaffolds present properties as high porosity, high degree swelling and good stability which make them suitable of applications as biomaterials.

Bian S., He M., Sui J., Cai H., Sun Y., Liang J., Fan Y., Zhang X.

• Thiolated hyaluronic acid (HA-SH) hydrogel was obtained by a single component and formed by the self-crosslinking of two free thiol groups. • No chemical additives, cytotoxic crosslinking and byproducts were added and produced in experiment. • The gelation time, swelling property, mechanical property and intelligent degradation behavior of the hydrogel could be controlled. • The characterizations of controllable self-crosslinking HA-SH hydrogels has great potential to meet the requirement of biomaterials applied in different fields of biomedicine. Although the disulfide bond crosslinked hyaluronic acid hydrogels have been reported by many research groups, the major researches were focused on effectively forming hydrogels. However, few researchers paid attention to the potential significance of controlling the hydrogel formation and degradation, improving biocompatibility, reducing the toxicity of exogenous and providing convenience to the clinical operations later on. In this research, the novel controllable self-crosslinking smart hydrogels with in-situ gelation property was prepared by a single component, the thiolated hyaluronic acid derivative (HA-SH), and applied as a three-dimensional scaffold to mimic native extracellular matrix (ECM) for the culture of fibroblasts cells (L929) and chondrocytes. A series of HA-SH hydrogels were prepared depending on different degrees of thiol substitution (ranging from 10 to 60%) and molecule weights of HA (0.1, 0.3 and 1.0M Da). The gelation time, swelling property and smart degradation behavior of HA-SH hydrogel were evaluated. The results showed that the gelation and degradation time of hydrogels could be controlled by adjusting the component of HA-SH polymers. The storage modulus of HA-SH hydrogels obtained by dynamic modulus analysis (DMA) could be up to 44.6 kPa. In addition, HA-SH hydrogels were investigated as a three-dimensional scaffold for the culture of fibroblasts cells (L929) and chondrocytes cells in vitro and as an injectable hydrogel for delivering chondrocytes cells in vivo . These results illustrated that HA-SH hydrogels with controllable gelation process, intelligent degradation behavior, excellent biocompatibility and convenient operational characteristics supplied potential clinical application capacity for tissue engineering and regenerative medicine.

Miles K.B., Ball R.L., Matthew H.W.

To improve the mechanical properties of chitosan (Ct) materials without the use of cytotoxic crosslinkers, disulfide cross-linkable Ct was synthesized by grafting N-acetyl-cysteine (NAC) to Ct using carbodiimide chemistry. Cast films of NAC-Ct conjugates were prepared with degrees of substitution (DS) of 0%, 6%, 15%, and 20%, and the disulfide bond formation was induced by increasing the reaction media pH to 11. The tensile strength, breaking strain, elastic moduli and toughness of disulfide cross-linked polymers were analyzed by monotonic tensile testing of hydrated NAC-Ct films. Crystallinity was determined via XRD. Results demonstrated that NAC incorporation and crosslinking in chitosan produced tougher polymer films with 4-fold higher tensile strength (10 MPa) and 6-fold greater elongation (365%), but reduced crystallinity, compared to unmodified chitosan. The resilience of NAC-Ct films was evaluated by cyclic testing, and results demonstrate that increasing NAC content produced a more resilient material that dissipated less energy when deformed. These improved mechanical properties broaden chitosan's applicability towards the construction of mechanically robust implantable scaffolds for tissue regeneration.

Amir M.N., Julkapli N.M., Abd Hamid S.B.

It is demonstrated that single titanium dioxide (TiO2) has high potential for photodegradation of pollutants. However, it is still far from becoming an effective photocatalyst system, due to issues of adsorption process, separation, as well as dissolution. Therefore, this study highlights the high adsorption capacity, simplified separation, and the promising stability of TiO2(SY) (synthesized via sol–gel method) photocatalyst, fabricated using chitosan–TiO2(SY) and supported by glass substrate (Cs–TiO2(SY)/glass substrate) photocatalysts. Chitosan (Cs), with abundant –R–NH and NH2 groups, promotes the adsorption sites of methyl orange (MO) and OH groups for major attachment to TiO2(SY). Meanwhile, the glass substrate increases stability and assists separation of the photocatalysts. Initially, nano-TiO2(SY) has been characterized using high-resolution transmission electron microscope. Cs–TiO2(SY)/glass substrate was fabricated via dip-coating. The distribution and interface between the photocatalytic components were characterized by Fourier transform infrared absorption spectroscopy, UV–Vis diffuse reflectance spectroscopy, field emission scanning electron microscopy, and energy-dispersive spectrometer. UV–Vis analysis of the multilayer photocatalyst (2, 4, 6, and 8 layers) was further carried out by the adsorption–photodegradation, with MO as model of pollutant. Seventy percent of the total removal of MO via optimized eight layers of photocatalyst was achieved within 1 h of UV irradiation. The adsorption photocatalyst achieved 50 % with no exposure to UV light for 15 min of irradiation. It is concluded that suitable photocatalytic conditions and sample parameters possessing the multilayer photocatalyst of Cs–TiO2(SY) are beneficial toward the adsorption–photodegradation process in wastewater treatment.

Zhang Y., Avery R.K., Vallmajo-Martin Q., Assmann A., Vegh A., Memic A., Olsen B.D., Annabi N., Khademhosseini A.

Elastin-like polypeptides (ELPs) are promising for biomedical applications due to their unique thermoresponsive and elastic properties. ELP-based hydrogels have been produced through chemical and enzymatic crosslinking or photocrosslinking of modified ELPs. Herein, a photocrosslinked ELP gel using only canonical amino acids is presented. The inclusion of thiols from a pair of cysteine residues in the ELP sequence allows disulfide bond formation upon exposure to UV light, leading to the formation of a highly elastic hydrogel. The physical properties of the resulting hydrogel such as mechanical properties and swelling behavior can be easily tuned by controlling ELP concentrations. The biocompatibility of the engineered ELP hydrogels is shown in vitro as well as corroborated in vivo with subcutaneous implantation of hydrogels in rats. ELP constructs demonstrate long-term structural stability in vivo, and early and progressive host integration with no immune response, suggesting their potential for supporting wound repair. Ultimately, functionalized ELPs demonstrate the ability to function as an in vivo hemostatic material over bleeding wounds.

Das D., Ghosh P., Ghosh A., Haldar C., Dhara S., Panda A.B., Pal S.

A novel stimulus-sensitive covalently cross-linked hydrogel derived from dextrin, N-isopropylacrylamide, and N,N'-methylene bis(acrylamide) (c-Dxt/pNIPAm), has been synthesized via Michael type addition reaction for controlled drug release application. The chemical structure of c-Dxt/pNIPAm has been confirmed through Fourier transform infrared (FTIR) spectroscopy and (1)H and (13)C NMR spectral analyses. The surface morphology of the hydrogel has been studied by field emission scanning electron microscopic (FE-SEM) and environmental scanning electron microscopic (E-SEM) analyses. The stimulus responsiveness of the hydrogel was studied through equilibrium swelling in various pH media at 25 and 37 °C. Rheological study was performed to measure the gel strength and gelation time. Noncytotoxicity of c-Dxt/pNIPAm hydrogel has been studied using human mesenchymal stem cells (hMSCs). The biodegradability of c-Dxt/pNIPAm was confirmed using hen egg lysozyme. The in vitro and in vivo release studies of ornidazole and ciprofloxacin imply that c-Dxt/pNIPAm delivers both drugs in a controlled way and would be an excellent alternative for a dual drug carrier. The FTIR, powder X-ray diffraction (XRD), and UV-vis-near infrared (NIR) spectra along with the computational study predict that the drugs remain in the matrix through physical interaction. A stability study signifies that the drugs (ornidazole ∼97% and ciprofloxacin ∼98%) are stable in the tablet formulations for up to 3 months.

Soledad Lencina M.M., Iatridi Z., Villar M.A., Tsitsilianis C.

Three samples of sodium alginate grafted by amino-terminated PNIPAM (low and high molecular weight poly(N-isopropylacrylamide)) and a random P(NIPAM-co-NtBAM) (NtBAM: N-tertiary butyl acrylamide) copolymer, were synthesized via the carbodiimide chemistry and their temperature-induced hydrogelation capability was evaluated by rheology. All the samples showed thermothickening behaviour depending on concentration, ionic strength and hydrophobic comonomer content, incorporated to the PNIPAM thermo-sensitive pendant chains. The main result of this study was that a slight hydrophobic enrichment (just 15 mol% NtBAM) of PNIPAM was sufficient to shift the gelation temperature well below the physiological temperature at 32 °C and at the lowest polymer concentration studied (i.e. 10 wt%). The consequence of that was that the ALG-g-P(NIPAM-co-NtBAM) graft copolymer hydrogel exhibited the best rheological thermo-responsive properties and might be used as injectable hydrogel for potential applications in biomedicine.

Mellati A., Dai S., Bi J., Jin B., Zhang H.

Chitosan-g-poly(N-isopropylacrylamide) was synthesized as a stem cell mimicking microenvironment. Solubility and gel mechanical strength were optimised through manipulating the grafting parameters.

Liu X., Chen Y., Huang Q., He W., Feng Q., Yu B.

In order to get a water-soluble in situ gel-forming system, a thiolated chitosan, chitosan-4-thio-butylamidine (CS-TBA) conjugate was synthesized and used to replace the unmodified chitosan in the application of the in situ gel-forming system. A novel thermo-sensitive hydrogel was prepared based on CS-TBA/hydroxyapatite (HA)/beta-glycerophosphate disodium (β-GP). The gel formation, rheological properties, morphology, degradation, cytotoxicity, as well as protein release process of the novel gel system were investigated in this study. The CS-TBA/HA/β-GP gel showed a higher storage modulus (G') and loss modulus (G″) and a decreased bovine serum albumin (BSA) release rate which was maintained the protein release for a longer time compared with the unmodified chitosan (CS)/HA/β-GP gel, due to the existence of thiol groups and/or disulfide bonds. The CS-TBA/HA/β-GP gel has a porous structure with a uniform distribution of nano-hydroxyapatite, an appropriate degradation rate and low cytotoxicity, showing potential applications in drug delivery and tissue engineering.

Eskandarinia A., Navid S., Salami M.A., Ghasemi Y., Heydari R., Haghdel M., Zhang H., Samadi A.

Duymaz D., Kebabci A.O., Kizilel S.

Feng S., Niu L., Wang X., Zhang Q., you R., Li M., Feng Y.

Huang Y., Li Z., Ranaweera C., Jayathilaka P.B., Islam M.S., Ajam A., Silberstein M.N., Kilian K.A., Kruzic J.J.

Liu Z., Ma X., Liu J., Zhang H., Fu D.

Ching P.C., Chang Y., Weng C., Wang J., Yeh M.

Pesaran Afsharian Y., Rahimnejad M., Rabiee S.M., Feizi F., Seitz H.

AbstractThe incidence of type 2 diabetes (T2DM) increases significantly worldwide. Due to consistent hyperglycemia, insulin resistance, and chronic inflammation, T2DM patients encounter osteoporosis and induced osteoporotic fracture risks. Antidiabetic drugs have been traditional therapies that seek to control blood glucose, balance bone metabolism, and favor systemic immunosuppression. However, such drugs impact bone quality and its nano‐scale features in the long‐term. Today, biomedical experts are continuously advancing drug delivery tools for local delivery of osteo‐immunomodulatory agents in T2DM. It is demonstrated that bioavailability and release profile determine osteo‐immunomodulatory and osteoconductivity outcomes of such therapeutics. This review focuses on introducing currently used local drug delivery vehicles in T2DM. The fabrication techniques of such biomaterial‐based systems are thoroughly examined. Furthermore, the feasibility and the potential factors contributing to consistent release of bioactive agents are surveyed. Furthermore, the extent of in vivo responses is described in the context of current research examples. Targeted signaling mechanisms are also assessed in detail to elucidate the activated healing routes.

Savicke M., Peciulyte L., Bendoraitiene J., Samaryk V., Rutkaite R.

Acenaphthylene-labelled chitosan-graft-poly(N-isopropylacrylamide) (CS-g-PNIPAAm-ACE) copolymers of different composition were synthesized by free-radical polymerization of chitosan (CS), N-isopropylacrylamide (NIPAAm) and acenaphthylene (ACE) in aqueous solution using potassium persulfate (PPS) as an initiator. By changing the molar ratio of CS:NIPAAm:ACE from 1:0.25:0.0125 to 1:10:0.11 the ACE-labelled copolymers with different content of poly(N-isopropylacrylamide) (PNIPAAm) grafts were prepared. The chemical structure of the obtained CS-g-PNIPAAm-ACE copolymers was confirmed by FT-IR and 1H NMR spectroscopy. In addition, 1H NMR spectra were also used to calculate the content of CS and NIPAAm in the synthesized copolymers. The introduction of ACE label into PNIPAAm grafts was also achieved as confirmed by UV spectroscopy. Moreover, the lower critical solution temperature (LCST) behaviour of synthesized copolymers was assessed by cloud point, differential scanning calorimetry (DSC) analysis, particle size, zeta potential and steady-state fluorescence measurements. The aqueous solutions of copolymers containing ≥ 26.5 molar percent of PNIPAAm side chains demonstrated LCST behaviour with the phase separation at around 29.3–31.3 °C. The intensity of thermoresponsiveness depended on the composition of copolymers and was higher for the copolymers with higher content of poly(N-isopropylacrylamide) moieties. Moreover, ACE chromophore attached to PNIPAAm grafts served as a fluorescent marker in the steady-state fluorescence investigation of thermoresponsive behaviour of synthesized copolymers.

Xu L.

Promdontree P., Ounkaew A., Yao Y., Zeng H., Narain R., Ummartyotin S.

Injectable and temperature-responsive Poly(N-Isopropylacrylamide) (PNIPAAm)/Chitosan composite hydrogels reinforced with cellulose nanocrystals (CNCs) were successfully fabricated via photopolymerization. 0.1–3% (w/v) of cellulose nanocrystals were incorporated into the PNIPAAm/chitosan matrix to form thermo-responsive injectable composite hydrogels. FT-IR spectra confirmed the successful formation of these hydrogels, highlighting the characteristic peaks PNIPAAm, chitosan and CNCs. The inclusion of CNCs led to a reduced pore size as compared to the control hydrogels. The mechanical properties of the hydrogel were characterized under various temperature conditions. Rheology tests showed that storage modulus (G′) increased significantly above 30 °C, indicating gel-like behavior. Thermogravimetric analysis showed thermal stability up to 300 °C. The volume phase transition temperatures (VPTT) of the hydrogels were found to be in the range of 34–38 °C, close to physiological body temperature. The equilibrium swelling ratio (ESR) of the CNC-containing hydrogels was higher than that of the control. In vitro studies with Human Dermal Fibroblast adult (HDFa) cells showed the hydrogels to be non-toxic, suggesting their potential for biomedical applications.

Lin T., Wang H., Tseng Y., Yeh M.

Articular cartilage regeneration is a major challenge in orthopedic medicine. Endothelial progenitor cells (EPCs) are a promising cell source for regenerative medicine applications. However, their roles and functions in cartilage regeneration are not well understood. Additionally, thermosensitive chitosan hydrogels have been widely used in tissue engineering, but further development of these hydrogels incorporating vascular lineage cells for cartilage repair is insufficient. Thus, this study aimed to characterize the ability of EPCs to undergo endothelial-mesenchymal stem cell transdifferentiation and chondrogenic differentiation and investigate the ability of chondrogenic EPC-seeded thermosensitive chitosan-graft-poly (

Enoch K., S R., Angayarkanni S.A.

Biomaterials that mimic biological tissues are in great demand in tissue engineering. Hydrogels are rising as a conducive candidate in tissue engineering on account of their water-holding capacity, mechanical strength, and elasticity. Nevertheless, the development of hydrogels that mimic biological tissues with the desired stability and mechanical strength, remains a notable barrier. In this investigation, chitosan/alginate hydrogels were prepared by tuning the chitosan concentration from 0.5 to 2.5%w/v with a fixed 1%w/v alginate concentration using 0.1% glutaraldehyde as a gelling agent. The hydrogel system forms through covalent bonding between chitosan and alginate, mediated by aldehyde groups of the glutaraldehyde. The mechanical strength of the hydrogel was elucidated by probing its viscoelastic behavior through rheological analysis. The rheological investigations revealed that the prepared chitosan/alginate hydrogels are profoundly stable with shear-thinning characteristics. The increase in chitosan concentration enhanced the stability and viscoelastic attributes of the hydrogels. The yield stress values ranging from 0.93 kPa to 14.24 kPa indicate the possibility of using these hydrogels in bioadhesives and soft and bone tissue engineering. The complex modulus of the prepared chitosan/alginate hydrogels resembles the shear modulus of liver tissues, osteogenic cells, and articular cartilage, and hence, these hydrogels pose as suitable candidates in liver, bone, and cartilage tissue engineering. The chitosan/alginate hydrogels possess outstanding self-healing ability, along with biocompatibility, stability, and mechanical strength, rendering them highly advantageous for applications in biomedical tissue engineering and bioadhesives.

Yang K., Wu Z., Zhang K., Weir M.D., Xu H.H., Cheng L., Huang X., Zhou W.

Bone defects caused by tumors, osteoarthritis, and osteoporosis attract great attention. Because of outstanding biocompatibility, osteogenesis promotion, and less secondary infection incidence ratio, stimuli-responsive biomaterials are increasingly used to manage this issue. These biomaterials respond to certain stimuli, changing their mechanical properties, shape, or drug release rate accordingly. Thereafter, the activated materials exert instructive or triggering effects on cells and tissues, match the properties of the original bone tissues, establish tight connection with ambient hard tissue, and provide suitable mechanical strength. In this review, basic definitions of different categories of stimuli-responsive biomaterials are presented. Moreover, possible mechanisms, advanced studies, and pros and cons of each classification are discussed and analyzed. This review aims to provide an outlook on the future developments in stimuli-responsive biomaterials.

Kamel S., El-Sayed N.S.

Injectable hydrogels are gaining popularity among researchers due to their in situ gelation, passive targeting, and capability attributes that are needed to enable the homogenous inclusion of therapeutic molecules and/or cells without surgery. In addition, their superior biocompatibility and biodegradability encourage, very highly, their applicability in the biomedical and pharmaceutical fields with minimal adverse effects. Injectable hydrogels facilitate, in a controllable manner, the encapsulation and release of therapeutic agents, including drugs, proteins, genes, and cells. Different techniques have been reported for the preparation of stimuli-responsive injectable hydrogels, e.g., self-assembly, hydrophobic interactions, photo-polymerization, click chemistry, enzyme-mediated reactions, Schiff base reactions, Michael addition reactions, ionic interactions, guest–host inclusion, etc. This chapter covers the current cross-linking approaches that are often employed to fabricate smart injectable hydrogels.

Zeng H., Chen Q., Mo Z., Huang X., Zhou L.

AbstractSignificant advancements have been achieved in polymer nanogel synthesis, yet there is a dearth of methods for easily preparing size‐adjustable, surface‐modifiable, and biocompatible nanogels. This study introduces a straightforward method for fabricating hyperbranched polyglycerol (HPG) nanogels in water through self‐assembly and disulfide bond crosslinking, avoiding the use of surfactants. The process involves modifying HPG with thioctic acid (TA) to create amphiphilic HPG‐TA rich in disulfide bonds, which is then reduced to facilitate water introduction and self‐assembly. Photocrosslinking is used to finalize the formation of HPG nanogels. These nanogels feature a uniform size distribution, with hydrodynamic diameters tunable from around 90 to 400 nm by tweaking synthesis variables. They have shown low cytotoxicity and high stability in aqueous media, with notable sensitivity to pH, especially in acidic conditions (e.g., pH 3), and redox‐responsiveness, as evidenced by reactions to 10 mM dithiothreitol (DTT). The nanogels' multiple hydroxyl groups enable easy functionalization, exemplified by the synthesis of fluorescent HPG‐RB nanogels. This work presents an efficient strategy for producing robust HPG nanogels, potentially spurring further advancements in the field of polymer nanogel synthesis and application.