Biopolymer-based Hydrogels Research Articles

Bovine Serum Albumin Hydrogel Formation: pH Dependence and Rheological Analyses.

In vitro evaluation of the physical properties of biopolymer-based hydrogels can help in understanding certain phenomena, such as liquid-liquid phase separation. The formation of bovine serum albumin (BSA) hydrogels was investigated in the pH range of 1.0 to 4.0. Hydrogels were formed in the pH range of 3.0 to 4.0, whereas viscous solutions were formed in the pH range of 1.5 to 2.5. Unexpectedly, formation of BSA hydrogel was observed in extremely acidic condition (pH 1.0). The circular dichroism spectra of BSA solutions were recorded at pH values of 1.0, 2.0, 3.0, and 7.0, and α-helix contents were determined from the ellipticity data at 222 nm. The α-helix content decreased with a decrease in pH, and this decrease was associated with the partial denaturation (F-isoform) and the denaturation (E-isoform) of BSA. However, the α-helix contents at pH 1.0 and 3.0 were similar. BSA hydrogels at pH 1.0 and 3.5 showed similar dynamic viscoelastic properties, further supporting the stereo structural change of BSA from the denatured E-isoform to the partially denatured F-isoform at pH 1.0. The study also focused on measuring viscoelasticity, a fundamental physical property of hydrogels, using traditional rheometer and with minimal sample volume. A highly reproducible procedure for measuring the viscoelastic properties of hydrogels was established using sample volumes of 200 and 350 μL.

Recent Developments in Biopolymer-Based Hydrogels for Tissue Engineering Applications.

Hydrogels are being investigated for their application in inducing the regeneration of various tissues, and suitable conditions for each tissue are becoming more apparent. Conditions such as the mechanical properties, degradation period, degradation mechanism, and cell affinity can be tailored by changing the molecular structure, especially in the case of polymers. Furthermore, many high-functional hydrogels with drug delivery systems (DDSs), in which drugs or bioactive substances are contained in controlled hydrogels, have been reported. This review focuses on the molecular design and function of biopolymer-based hydrogels and introduces recent developments in functional hydrogels for clinical applications.

Nucleoside-Based Cross-Linkers for Hydrogels with Tunable Properties

Herein, we report bioderived cross-linkers to create biopolymer-based hydrogels with tunable properties. Nucleosides (inosine and uridine) and ribose (pentose sugar lucking the nitrogenous base) were partially oxidized to yield inosine dialdehyde (IdA), uridine dialdehyde (UdA), and ribose dialdehyde (RdA). The dialdehydes were further used as cross-linkers with polysaccharide chitosan to form hydrogels. Depending on the cross-linker type and concentration, the hydrogels showed tunable rheological, mechanical, and liquid holding properties allowing the preparation of injectable, soft, and moldable hydrogels. Computational modeling and molecular dynamics simulations shed light on hydrogel formation and revealed that, in addition to covalent bonding, noncovalent interactions (π-π stacking, cation-π, and H-bonding) also significantly contributed to the cross-linking process. To demonstrate various application possibilities, the prepared hydrogels were used as a growth platform for plant cells, as injectable inks for layer-by-layer 3D printing applications, and as moldable hydrogels for soft lithography to replicate the microstructure of the plant. These findings suggest that the obtained tunable biocompatible hydrogels have the potential to be good candidates for various biotechnological applications.

Biopolymer-Based Hydrogels for Harvesting Water from Humid Air: A Review

Despite the shrinkage of water availability worldwide, the water demand has been climbing due to the rapidly increasing human population and the impacts of numerous hydroclimatic factors. To feed the growing population and meet with the exigent need for freshwater, new water sources must be identified and utilized. In recent years, biopolymer-based hydrogels have been explored as a sustainable and inexpensive solution to capture moisture from humid air for water supply. This review summarizes recent advances in the preparation of atmospheric water harvesting hydrogels that are synthesized based on cellulose, chitosan, and/or other biopolymers, as well as their agricultural applications. The properties and performance of different biopolymer-based hydrogels are discussed and compared. Since agriculture accounts for more than 70% of the water consumption, developing a cost-effective hydrogel-based atmospheric water harvesting/supply system could be a promising solution for relieving the elevating water stress in arid and semi-arid regions.

Revolutionizing biomedicine: advancements, applications, and prospects of nanocomposite macromolecular carbohydrate-based hydrogel biomaterials: a review.

Nanocomposite hydrogel biomaterials represent an exciting Frontier in biomedicine, offering solutions to longstanding challenges. These hydrogels are derived from various biopolymers, including fibrin, silk fibroin, collagen, keratin, gelatin, chitosan, hyaluronic acid, alginate, carrageenan, and cellulose. While these biopolymers possess inherent biocompatibility and renewability, they often suffer from poor mechanical properties and rapid degradation. Researchers have integrated biopolymers such as cellulose, starch, and chitosan into hydrogel matrices to overcome these limitations, resulting in nanocomposite hydrogels. These innovative materials exhibit enhanced mechanical strength, improved biocompatibility, and the ability to finely tune drug release profiles. The marriage of nanotechnology and hydrogel chemistry empowers precise control over these materials' physical and chemical properties, making them ideal for tissue engineering, drug delivery, wound healing, and biosensing applications. Recent advancements in the design, fabrication, and characterization of biopolymer-based nanocomposite hydrogels have showcased their potential to transform biomedicine. Researchers are employing strategic approaches for integrating biopolymer nanoparticles, exploring how nanoparticle properties impact hydrogel performance, and utilizing various characterization techniques to evaluate structure and functionality. Moreover, the diverse biomedical applications of these nanocomposite hydrogels hold promise for improving patient outcomes and addressing unmet clinical needs.

Significance of biopolymer-based hydrogels and their applications in agriculture: a review in perspective of synthesis and their degree of swelling for water holding.

Hydrogels are three-dimensional polymer networks that are hydrophilic and capable of retaining a large amount of water. Hydrogels also can act as vehicles for the controlled delivery of active compounds. Bio-polymers are polymers that are derived from natural sources. Hydrogels prepared from biopolymers are considered non-toxic, biocompatible, biodegradable, and cost-effective. Therefore, bio-polymeric hydrogels are being extensively synthesized and used all over the world. Hydrogels based on biopolymers finds important applications in the agricultural field where they are used as soil conditioning agents as they can increase the water retention ability of soil and can act as a carrier of nutrients and other agrochemicals. Hydrogels are also used for the controlled delivery of fertilizer to plants. In this review, bio-polymeric hydrogels based on starch, chitosan, guar gum, gelatin, lignin, and alginate polymer have been discussed in terms of their synthesis method, swelling behavior, and possible agricultural application. The urgency to address water scarcity and the need for sustainable water management in agriculture necessitate the exploration and implementation of innovative solutions. By understanding the synthesis techniques and factors influencing the swelling behavior of these hydrogels, we can unlock their full potential in fostering sustainable agriculture and mitigating the challenges posed by an ever-changing environment.

Chitosan and carboxymethyl cellulose-based 3D multifunctional bioactive hydrogels loaded with nano-curcumin for synergistic diabetic wound repair

Biopolymer-based thermoresponsive injectable hydrogels with multifunctional tunable characteristics containing anti-oxidative, biocompatibility, anti-infection, tissue regeneration, and/or anti-bacterial are of abundant interest to proficiently stimulate diabetic wound regeneration and are considered as a potential candidate for diversified biomedical application but the development of such hydrogels remains a challenge. In this study, the Chitosan-CMC-g-PF127 injectable hydrogels are developed using solvent casting. The Curcumin (Cur) Chitosan-CMC-g-PF127 injectable hydrogels possess viscoelastic behavior, good swelling properties, and a controlled release profile. The degree of substitution (% DS), thermal stability, morphological behavior, and crystalline characteristics of the developed injectable hydrogels is confirmed using nuclear magnetic resonance (1H NMR), thermogravimetric analysis, scanning electron microscopy (SEM), and x-ray diffraction analysis (XRD), respectively. The controlled release of cur-micelles from the hydrogel is evaluated by drug release studies and pharmacokinetic profile (PK) using high-performance liquid chromatography (HPLC). Furthermore, compared to cur micelles the Cur-laden injectable hydrogel shows a significant increase in half-life (t1/2) up to 5.92 ± 0.7 h, mean residence time (MRT) was 15.75 ± 0.76 h, and area under the first moment curve (AUMC) is 3195.62 ± 547.99 μg/mL*(h)2 which reveals the controlled release behavior. Cytocompatibility analysis of Chitosan-CMC-g-PF127 hydrogels using 3T3-L1 fibroblasts cells and in vivo toxicity by subcutaneous injection followed by histological examination confirmed good biocompatibility of Cur-micelles loaded hydrogels. The histological results revealed the promising tissue regenerative ability and shows enhancement of fibroblasts, keratinocytes, and collagen deposition, which stimulates the epidermal junction. Interestingly, the Chitosan-CMC-g-PF127 injectable hydrogels ladened Cur exhibited a swift wound repair potential by up-surging the cell migration and proliferation at the site of injury and providing a sustained drug delivery platform for hydrophobic moieties.

Dynamically bonded, tough, and conductive MXene@oxidized sodium alginate: chitosan based multi-networked elastomeric hydrogels for physical motion detection

Biopolymer-based conductive hydrogels (HGs) are promising candidates for preparing environmentally friendly flexible electronics. However, it is still a great challenge to synthesize biopolymer-based tough, self-healable, and fast strain recoverable HGs. Herein, a facile strategy is demonstrated to synthesize stretchable, self-recoverable, conductive, and tough HGs strain sensors through the formation of multi-dynamic interactions (i.e., imine bond formation, hydrogen bonds, ionic bonds, and electrostatic bonds) and strong covalent interactions between MXene (Ti3C2Tx), oxidized sodium alginate (OSA), chitosan (CS), polyacrylamide (PAAm), Fe(III) and PEDOT:PSS. Thus, obtaining dynamically and covalently bonded nanocomposite hydrogels (NCHGs) with controllable interfacial interactions exhibited a high mechanical strength (0.91 MPa), toughness (2.99 MJ/m3), stretchability (820 %), elasticity (>600 %) and conductivity (1.31 S/m). In addition, the presence of Fe(III) ions and conducting fillers endows excellent repeatability with high stability in resistance change upon bending or stretching with ultra-broad sensitivity up to 11-gauge factor and consisting lowest resistance change up to 0.5 %.

Dexamethasone loaded injectable, self-healing hydrogel microspheres based on UPy-functionalized Gelatin/ZnHAp physical network promotes bone regeneration

Biopolymer-based injectable hydrogels provide great potential as bone tissue engineering (BTE) scaffolds on account of biocompatibility, and pore interconnectivity that enables delivery of cells and/or signaling molecules for bone repair. Recently, Gelatin hydrogels based on H-bonds were considered in response to concerns around the chemical crosslinking agents. In this study, a self-healing gelatin hydrogel with remarkable compressive and self-healing properties was prepared via formation of quadruple hydrogen bonds between ureidopyrimidinon functional groups, which were substituted on NH2 groups of gelatin(GelUPy). Degree of substitution controls properties of the resulting hydrogel from a shape- memory hydrogel (100% substitution), to a hydrogel (about 80%), to this self-healing hydrogel (about 40%). We report a strategy that adopts an emulsion synthesis approach to delivery of dexamethasone and Ca/Zn ions from injectable self-healing GelUPy hydrogel (GelUPy-ZnHApUPy-DEX), to induce osteogenic differentiation of adipose-derived stem cells, in vitro, and enhance bone regeneration in a cranial bone defect in a rat model. We show that key properties of the composite hydrogels, including mechanical properties, and release behavior of DEX are a match to the requirements of BTE. Overall, our results demonstrate that this self-healing gelatin approach is a promising strategy to enhance bone regeneration through a minimally invasive procedure.

Directed Evolution Enables Simultaneous Controlled Release of Multiple Therapeutic Proteins from Biopolymer-Based Hydrogels.

With the advent of increasingly complex combination strategies of biologics, independent control over their delivery is the key to their efficacy; however, current approaches are hindered by the limited independent tunability of their release rates. To overcome these limitations, directed evolution is used to engineer highly specific, low affinity affibody binding partners to multiple therapeutic proteins to independently control protein release rates. As a proof-of-concept, specific affibody binding partners for two proteins with broad therapeutic utility: insulin-like growth factor-1 (IGF-1) and pigment epithelium-derived factor (PEDF) are identified. Protein-affibody binding interactions specific to these target proteins with equilibrium dissociation constants (KD ) between 10-7 and 10-8 m are discovered. The affibodies are covalently bound to the backbone of crosslinked hydrogels using click chemistry, enabling sustained, independent, and simultaneous release of bioactive IGF-1 and PEDF over 7 days. The system is tested with C57BL/6J mice in vivo, and the affibody-controlled release of IGF-1 results in sustained activity when compared to bolus IGF-1 delivery. This work demonstrates a new, broadly applicable approach to tune the release of therapeutic proteins simultaneously and independently and thus the way for precise control over the delivery of multicomponent therapies is paved.

A high-conductive, anti-freezing, antibacterial and anti-swelling starch-based physical hydrogel for multifunctional flexible wearable sensors

Flexible wearable sensors based on conductive hydrogels are attracting increasing interest. To meet the urgent demands of sustainability and eco-friendliness, biopolymer-based physically crosslinked hydrogels have drawn great attention. Starch has a great potential due to its renewability, biocompatibility, nontoxicity and low cost. However, poor mechanical property, low conductivity and lack of versatility are seriously limiting the applications of starch-based hydrogels in wearable sensors. Moreover, the development of starch hydrogel-based wearable sensors in harsh conditions remains a challenge. Herein, multifunctional and physical crosslinking hydrogels were developed by introducing ionic liquid (1-ethyl-3-methyl imidazolium acetate) and metal salt (AlCl3) into starch/polyvinyl alcohol double-network structure. The hydrogel exhibited excellent stretchability (567%), tensile strength (0.53 MPa), high conductivity (2.75 S·m−1), good anti-freezing, antibacterial and anti-swelling properties. A wearable sensor assembled from the starch-based hydrogel exhibited a wide working range, high sensitivity (gauge factor: 5.93) and excellent reversibility. Due to the versatility, the sensor effectively detected human motion in normal and underwater environment, and possessed a sensitive pressure and thermal response. Overall, the present work provided a promising route to develop multifunctional and “green” biopolymer-based hydrogels for wearable sensors in human health and sporting applications.

Novel biopolymer-based hydrogels obtained through crosslinking of keratose proteins using tetrakis(hydroxymethyl) phosphonium chloride

Novel biopolymer-based hydrogels obtained through crosslinking of keratose proteins using tetrakis(hydroxymethyl) phosphonium chloride

Sodium alginate-f-GO composite hydrogels for tissue regeneration and antitumor applications

Biopolymer-based composite hydrogels have attracted tremendous attention for tissue regeneration and antitumor applications. Since sodium alginate is a biopolymer, they offer excellent therapeutic options with long-term drug release and low side effects. To prepare multifunctional composite hydrogels with anticancer and tissue regeneration capabilities, sodium alginate (SA) and graphene oxide (GO) were covalently linked and crosslinked with tetraethyl orthosilicate (TEOS) by the solvothermal method. The structural and morphological results show that the hydrogels exhibit the desired functionality and porosity. The swelling of hydrogels in an aqueous and PBS medium was investigated. SGT-4 had the highest swelling in both aqueous and PBS media. Swelling and biodegradation of the hydrogel were inversely related. The drug release of SGT-4 was determined in different pH media (pH 6.4, 7.4, and 8.4) and the kinetics of drug release was determined according to the Higuchi model (R2 = 0.93587). Antibacterial activities were evaluated against severe infectious agents. Uppsala (U87) and osteoblast (MC3T3-E1) cell lines were used to determine the anticancer and biocompatibility of the composite hydrogels, respectively. These results suggest that the composite hydrogels could be used as potential biomaterials for tissue regeneration and antitumor applications.

Bacterial Alginate-Based Hydrogel Reduces Hydro-Mechanical Soil-Related Problems in Agriculture Facing Climate Change

Agricultural systems are facing the negative impacts of erosion and water scarcity, directly impacting the hydro-mechanical behavior of soil aggregation. Several technologies have been proposed to reduce hydro-mechanical soil-related problems in agriculture. Biopolymer-based hydrogels have been reported to be a great tool to tackle these problems in soils. In this study, we investigated the hydro-mechanical behavior of different soils media treated with Ca-bacterial alginate hydrogel. We used an unconfined uniaxial compression test, aggregate stability test and hydraulic conductivity measurements to investigate the mechanical and hydraulic behavior of treated soils media. Our results from unconfined uniaxial compression test showed that yield stress (i.e., strength) increased in treated soils with higher kaolinite and water content (i.e., HCM3), compared with untreated coarse quartz sand (i.e., CM1). Furthermore, we found that temperature is an important factor in the gelation capacity of our hydrogel. At room temperature, HCM3 displayed the higher aggregate stability, almost 5.5-fold compared with treated coarse quartz sand (HCM1), while this differential response was not sustained at warm temperature. In general, the addition of different quantities of kaolinite decreased the saturated hydraulic conductivity for all treatments. Finally, bright field microscopy imaging represents the soil media matrix between sand and clay particles with Ca-bacterial alginate hydrogel that modify the hydro-mechanical behavior of different soils media. The results of this study could be helpful for the soil-related problems in agriculture facing the negative effects of climate change.

Recent Progress in Biopolymer-Based Hydrogel Materials for Biomedical Applications.

Hydrogels from biopolymers are readily synthesized, can possess various characteristics for different applications, and have been widely used in biomedicine to help with patient treatments and outcomes. Polysaccharides, polypeptides, and nucleic acids can be produced into hydrogels, each for unique purposes depending on their qualities. Examples of polypeptide hydrogels include collagen, gelatin, and elastin, and polysaccharide hydrogels include alginate, cellulose, and glycosaminoglycan. Many different theories have been formulated to research hydrogels, which include Flory-Rehner theory, Rubber Elasticity Theory, and the calculation of porosity and pore size. All these theories take into consideration enthalpy, entropy, and other thermodynamic variables so that the structure and pore sizes of hydrogels can be formulated. Hydrogels can be fabricated in a straightforward process using a homogeneous mixture of different chemicals, depending on the intended purpose of the gel. Different types of hydrogels exist which include pH-sensitive gels, thermogels, electro-sensitive gels, and light-sensitive gels and each has its unique biomedical applications including structural capabilities, regenerative repair, or drug delivery. Major biopolymer-based hydrogels used for cell delivery include encapsulated skeletal muscle cells, osteochondral muscle cells, and stem cells being delivered to desired locations for tissue regeneration. Some examples of hydrogels used for drug and biomolecule delivery include insulin encapsulated hydrogels and hydrogels that encompass cancer drugs for desired controlled release. This review summarizes these newly developed biopolymer-based hydrogel materials that have been mainly made since 2015 and have shown to work and present more avenues for advanced medical applications.

Controlled Release in Hydrogels Using DNA Nanotechnology.

Gelatin is a biopolymer widely used to synthesize hydrogels for biomedical applications, such as tissue engineering and bioinks for 3D bioprinting. However, as with other biopolymer-based hydrogels, gelatin-hydrogels do not allow precise temporal control of the biomolecule distribution to mimic biological signals involved in biological mechanisms. Leveraging DNA nanotechnology tools to develop a responsive controlled release system via strand displacement has demonstrated the ability to encode logic process, which would enable a more sophisticated design for controlled release. However, this unique and dynamic system has not yet been incorporated within any hydrogels to create a complete release circuit mechanism that closely resembles the sequential distribution of biomolecules observed in the native environment. Here, we designed and synthesized versatile multi-arm DNA motifs that can be easily conjugated within a gelatin hydrogel via click chemistry to incorporate a strand displacement circuit. After validating the incorporation and showing the increased stability of DNA motifs against degradation once embedded in the hydrogel, we demonstrated the ability of our system to release multiple model cargos with temporal specificity by the addition of the trigger strands specific to each cargo. Additionally, we were able to modulate the rate and quantity of cargo release by tuning the sequence of the trigger strands.

Biofunctional Hyaluronic Acid/κ-Carrageenan Injectable Hydrogels for Improved Drug Delivery and Wound Healing.

The in situ injectable hydrogel system offers a widespread range of biomedical applications in prompt chronic wound treatment and management, as it provides self-healing, maintains a moist wound microenvironment, and offers good antibacterial properties. This study aimed to develop and evaluate biopolymer-based thermoreversible injectable hydrogels for effective wound-healing applications and the controlled drug delivery of meropenem. The injectable hydrogel was developed using the solvent casting method and evaluated for structural changes using proton nuclear magnetic resonance, Fourier transforms infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The results indicated the self-assembly of hyaluronic acid and kappa-carrageenan and the thermal stability of the fabricated injectable hydrogel with tunable gelation properties. The viscosity assessment indicated the in-situ gelling ability and injectability of the hydrogels at various temperatures. The fabricated hydrogel was loaded with meropenem, and the drug release from the hydrogel in phosphate buffer saline (PBS) with a pH of 7.4 was 96.12%, and the simulated wound fluid with a pH of 6.8 was observed to be at 94.73% at 24 h, which corresponds to the sustained delivery of meropenem. Antibacterial studies on P. aeruginosa, S. aureus, and E. coli with meropenem-laden hydrogel showed higher zones of inhibition. The in vivo studies in Sprague Dawley (SD) rats presented accelerated healing with the drug-loaded injectable hydrogel, while 90% wound closure with the unloaded injectable hydrogel, 70% in the positive control group (SC drug), and 60% in the negative control group was observed (normal saline) after fourteen days. In vivo wound closure analysis confirmed that the developed polymeric hydrogel has synergistic wound-healing potential.

Injectable Organic-Inorganic Biocomposites for Bone Tissue Regeneration - A Mini Review

Bone regeneration is complex physiological process, which include the most common form of regeneration - bone fracture healing and new bone formation. Moreover, large bone defects, infections and bone diseases such as osteoporosis and arthritis can impair bone regeneration. Despite intensive research and development of biomaterials for bone tissue engineering, especially for osteoporotic bone healing, the properties of the fabricated biomaterials are still far from those of unique composite structure of natural bone and desired therapeutic effect not achieved. This mini-review will highlight the various cutting-edge injectable inorganic-organic biocomposites as minimally invasive and regenerative therapeutics for bone tissue regeneration. The review will summarize the main strategic tools for the development of injectable biocomposites: natural or synthetic biopolymer-based hydrogels, bioactive inorganic fillers and biologically active components, as well as the fabrication techniques and synthesis methods.

Facile preparation of cellulose hydrogel with Achilles tendon-like super strength through aligning hierarchical fibrous structure

The extreme mechanical strength of fibrous connective tissues in the human body, such as ligaments and tendons, has always been challenging for hydrogel scientists. Here, we created extremely strong, purely cellulose-based hydrogels (DCC-E gels). The fracture stress and Young’s modulus of the gels were improved to the level of an Achilles tendon even at their equilibrium swollen state. To make DCC-E gels, regenerated cellulose gels were first prepared with ethanol as the anti-solvent. DCC-E gels were then prepared by applying Drying in Confined Condition method, where regenerated cellulose gels were prestretched and dried while their length was fixed. Although strength improvement of materials is typically only achieved at the expense of toughness, a significant increase in strength was achieved while maintaining high levels of toughness. The high strength and toughness of the DCC-E gels were realized by optimizing the cellulose fibril arrangement from nanoscale to macroscale, which was done by selection of an appropriate solvent used for cellulose regeneration. Parallel aggregated fibrous structures observed in the DCC-E gels are thought to play a central role in the enhancement of both toughness and strength. This study can assist in expanding the application of biopolymer-based hydrogels in tissue engineering and soft electronics.

Covalent and environment-responsive biopolymer hydrogel for drug delivery and wound healing

Biopolymer-based hydrogels are important cell scaffolding materials for drug delivery and regenerative medicine. In this study, we report a covalently cross-linked composite chitosan-alginate hydrogel possessing pH sensitivity to degradation for drug delivery. To enhance mechanical strength of hydrogel, polyvinyl alcohol (PVA) was also added to form hydrogen bonds with polysaccharides under physiological condition. The gelation mechanism is attributed to the Schiff-base reaction occurring between amino groups in carboxymethyl chitosan (CMCS) and aldehyde groups in oxidized sodium alginate (OAlg). Synchronously, to enhance antibacterial properties of biomaterials, 5-fluorouracil (5-Flu) was mechanically mixed in the PVA solution, followed by incorporation into the CMCS-OAlg hydrogel to form a composite gel scaffold. Molecular weight and concentration of PVA would affect the gelation morphology, mechanical properties, swelling ratio, in vitro degradation and pH sensitivity of the gel scaffold. The composite gel scaffold has good drug release and antibacterial properties through drug release calculation and antibacterial performance evaluation. These results indicate that the composite gel scaffold has great potential for pH-sensitive drug delivery and wound healing applications.