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Enzymatic Crosslinking to Fabricate Antioxidant Peptide-based Supramolecular Hydrogel for Improving Cutaneous Wound Healing
Abstract
Peptide-based supramolecular hydrogels are promising scaffold materials and have been utilized in many fields. The mechanical properties of peptide hdyrogels are usually enhanced by synthetic or natural polymers to expand their application scope. In this study, antioxidant supramolecular hydrogels based on feruloyl-modified peptide and glycol chitosan are fabricated via mild laccase-mediated crosslinking reaction. Natural polysaccharide derivative—feruloyl glycol chitosan (GC-Fer) was used to enhance the mechanical properties of peptide hydrogels. Feruloyl groups are introduced into gel matrix via covalent bonds, which endows hydrogel inherent antioxidant properties. This is benifical for their in vivo application via scavenging harmful free radicals existed in the cutaneous wound. The further in vivo experiments demonstrated that the feruloyl-containing antioxidant hydrogel can improve cutaneous wound healing process. Regeneration process of mature epithelium and connective tissue were accelerated in a full-thick skin defect model.
... Generally, the type of polymer crosslinking can be categorized into physical and chemical crosslinking (Figure 3). Physical crosslinking includes hydrogen and ionic bonds (Johnson et al., 2020), as well as hydrophobic (Wei et al., 2019), and supramolecular interactions (Zhao et al., 2020a). Physical crosslinking renders hydrogels self-healing and injectable due to their weak physical interactions. ...
... More recently, enzymatic crosslinking has received significant attention due to its high efficiency and specificity, while only requiring a relatively mild reaction condition ( Figure 3). The most widely investigated enzymatic crosslinking strategy is the reaction of phenol containing polymers catalyzed by horseradish peroxidase (HRP) (Tran et al., 2011;Lee et al., 2014;Liang et al., 2019a;Yao et al., 2019;Thi et al., 2020) or laccase (Wei et al., 2019). The bacterial transpeptidase Sortase A (SrtA) catalyzes polymer crosslinking enables that hydrogel formation and modification based on the ligation of LPXTGX (where X can be any amino acid except proline) and GGGG (Ham et al., 2016;Gau et al., 2017;Broguiere et al., 2018). ...
Wound healing is a common physiological process which consists of a sequence of molecular and cellular events that occur following the onset of a tissue lesion in order to reconstitute barrier between body and external environment. The inherent properties of hydrogels allow the damaged tissue to heal by supporting a hydrated environment which has long been explored in wound management to aid in autolytic debridement. However, chronic non-healing wounds require added therapeutic features that can be achieved by incorporation of biomolecules and supporting cells to promote faster and better healing outcomes. In recent decades, numerous hydrogels have been developed and modified to match the time scale for distinct stages of wound healing. This review will discuss the effects of various types of hydrogels on wound pathophysiology, as well as the ideal characteristics of hydrogels for wound healing, crosslinking mechanism, fabrication techniques and design considerations of hydrogel engineering. Finally, several challenges related to adopting hydrogels to promote wound healing and future perspectives are discussed.
... In this stage, collagen synthesis and collagen degradation take place continuously. Type III collagen degrades and replaces by type I collagen from the granulation tissue by metalloproteinase (MMPs) released from macrophages and fibroblasts (Wei et al., 2019). MMPs play an essential role in remodeling scar tissue by the reformation of the ECM. ...
... It is also called "Molecular self-assembly." Hydrogels formed by the supramolecular assembly has various biomedical applications such as tissue engineering (Saunders & Ma, 2019), wound healing (Wei et al., 2019;Xu et al., 2017;Yang et al., 2014). The rheological properties such as shear thinning kinetics and storage modulus determine the hydrogel's suitability for biomedical use. ...
Diabetes mellitus (DM) is an endocrine disorder that causes increased blood glucose than usual due to insulin impairment. In DM, several complications arise in which diabetic wound (DW) is the most devastating complication. About 25% of patients with DM expected to develop DWs in their lifetime and undergo limb amputations. Even though several treatments such as surgery, debridement, wound dressings, advanced therapies were available, the overall conclusion has been that with very few exceptions, patients still suffer from limitations like pain, frequent dress changing, high rates of failure, and cost involvement. Further, the treatments involving the delivery of therapeutic agents in treating DWs have limited success due to abnormal levels of proteases in the DW environment. In this backdrop, in situ gelling injectable hydrogels have gained special attention due to their easy encapsulation of therapeutic medications and prolonged release, filling the wound defect areas, ease of handling, and minimally invasive surgical procedures. Though the in situ gelling injectable hydrogels are developed a couple of decades ago, their use for treating DW has not yet been explored thoroughly. Thus, in this review, we have covered the sequential events of DW healing, pathophysiology, current treatments, and its limitations, along with a particular emphasis on the mechanism of action of these in situ gelling injectable hydrogels treating DWs.
... The properties of polypeptide hydrogels can be improved by group modification. Q. Wei et al. (2019) used enzyme-mediated linking of polypeptides modified by different groups to endow them with excellent mechanical properties and antioxidant properties. Synthesis of feruloyl-modified peptides via sequential coupling of Fmoc-protected l-amino acids, followed by further crosslinking of ethylene glycol chitosan mediated by a laccase that can oxidize the acyl groups in feruloyl. ...
Due to the unique and excellent biological, physical, and chemical properties of peptide hydrogels, their application in the biomedical field is extremely wide. The applications of peptide hydrogels are closely related to their unique responsiveness and excellent properties. However, its defects in mechanical properties, stability, and toxicity limit its application in the food field. In this review, we focus on the fabrication methods of peptide hydrogels through the physical, chemical, and biological stimulations. In addition, the functional design of peptide hydrogels by the incorporation with materials is discussed. Meanwhile, the excellent properties of peptide hydrogels such as the stimulus responsiveness, biocompatibility, antimicrobial properties, rheology, and stability are reviewed. Finally, the application of peptide hydrogel in the food field is summarized and prospected.
... Cosmetics 2023, 10, 38 2 of 12 three-dimensional network of L amino acid-based gelators. Wei et al. [21] reported a gel functionalized with ferulic acid with quite a high antioxidant efficiency and even improved cutaneous wound healing. ...
Antioxidants are important substances used in the cosmetic and pharmaceutical fields that are able to block free radicals. These compounds can be incorporated into formulations for many reasons, such as release over time or preservation of the formulation activity and applicability. In the present study, a low-molecular-weight gel made with Boc-L-DOPA(Bn)2-OH was studied as suitable material to host antioxidants and improve their activity. The solvent change (DMSO/H2O) in combination with temperature was the technological procedure for the preparation of the gel. Two different antioxidants were tested: (1) α-tocopherol and (2) postbiotics. The antioxidant activity of α-tocopherol and of the postbiotics in the gel, measured by the (2,2-diphenyl-1-picryl-hydrazyl radical (DPPH) assay, showed higher values than those in the pure solvent. The antioxidant activity of the gel with 0.8 w/v% of gelator and α-tocopherol in the concentration range of 5–100 µM was 2.7–1.1 times higher on average than in the pure solvent. In the case of both postbiotics, the biggest difference was observed at 30% of postbiotics in the gel with 0.5% of a gelator, when the antioxidant activity was 4.4 to 4.7 times higher than that in the pure solvent.
... 52 Wei et al. prepared an antioxidant supramolecular hydrogel based on feruloyl-modified peptides and glycol CS through a mild laccase-mediated cross-linking reaction. 53 The prepared feruloyl antioxidant hydrogel enhanced the regeneration of the epithelium and connective tissue. ...
Hydrogels are promising and widely utilized in the biomedical field. In recent years, the anti‐inflammatory function of hydrogel dressings has been significantly improved, addressing many clinical challenges presented in ongoing endeavours to promote wound healing. Wound healing is a cascaded and highly complex process, especially in chronic wounds, such as diabetic and severe burn wounds, in which adverse endogenous or exogenous factors can interfere with inflammatory regulation, leading to the disruption of the healing process. Although insufficient wound inflammation is uncommon, excessive inflammatory infiltration is an almost universal feature of chronic wounds, which impedes a histological repair of the wound in a predictable biological step and chronological order. Therefore, resolving excessive inflammation in wound healing is essential. In the past 5 years, extensive research has been conducted on hydrogel dressings to address excessive inflammation in wound healing, specifically by efficiently scavenging excessive free radicals, sequestering chemokines and promoting M1‐to‐M2 polarization of macrophages, thereby regulating inflammation and promoting wound healing. In this study, we introduced novel anti‐inflammatory hydrogel dressings and demonstrated innovative methods for their preparation and application to achieve enhanced healing. In addition, we summarize the most important properties required for wound healing and discuss our analysis of potential challenges yet to be addressed. We present an overview highlighting the recent achievements in anti‐inflammatory hydrogel dressings, from preparation mechanisms to application methods in wound healing. Categories of anti‐inflammatory hydrogel dressings are based on the specific mechanisms of anti‐inflammatory activities for which hydrogel dressings are created, for example scavenging excessive ROS, sequestering chemokines and promoting M1‐to‐M2 polarization of macrophages.
... Then, glycol CS-FA conjugate was enzymatically crosslinked with feruloyl-modified peptides to elaborate antioxidant hydrogels for cutaneous wound healing. The in vivo evaluation in a full-thick skin defect model showed an accelerated wound closure process and the formation of mature skin through promoting fibroblast migration and re-epithelization [157]. ...
Over the past thirty years, research has shown the huge potential of chitosan in biomedical applications such as drug delivery, tissue engineering and regeneration, cancer therapy, and antimicrobial treatments, among others. One of the major advantages of this interesting polysaccharide is its modifiability, which facilitates its use in tailor-made applications. In this way, the molecular structure of chitosan has been conjugated with multiple molecules to modify its mechanical, biological, or chemical properties. Here, we review the conjugation of chitosan with some bioactive molecules: hydroxycinnamic acids (HCAs); since these derivatives have been probed to enhance some of the biological effects of chitosan and to fine-tune its characteristics for its application in the biomedical field. First, the main characteristics of chitosan and HCAs are presented; then, the currently employed conjugation strategies between chitosan and HCAs are described; and, finally, the studied biomedical applications of these derivatives are discussed to present their limitations and advantages, which could lead to proximal therapeutic uses.
... They generally have better mechanical properties than physical crosslinking hydrogels [22]. Chemical crosslinking mainly includes photopolymerization [42][43][44], enzymatic crosslinking [45][46][47], and thermal polymerization [48,49]. ...
Owing to their excellent mechanical flexibility, electrical conductivity, and biocompatibility, conductive hydrogels (CHs) are widely used in the fields of energy and power, and biomedical technology. To arrive at a better understanding of the design methods and development trends of CHs, this paper summarizes and analyzes related research published in recent years. First, we describe the properties and characteristics of CHs. Using Scopus, the world’s largest abstract and citation database, we conducted a quantitative analysis of the related literature from the past 15 years and summarized development trends in the field of CHs. Second, we describe the types of CH network crosslinking and basic functional design methods and summarize the three-dimensional (3D) structure-forming methods and conductive performance tests of CHs. In addition, we introduce applications of CHs in the fields of energy and power, biomedical technology, and others. Lastly, we discuss several problems in current CH research and introduce some prospects for the future development of CHs.Graphic abstract
... The retained rhBMP-2 in the HPGC + BMP implant could localize osteoprogenitor recruitment and osteogenesis while also minimizing rhBMP-2 diffusion loss at the implantation site ( Figure 6). In addition, the enzymatic crosslinking reaction produces large quantities of entangled nanofibers, contributing to a denser network and smaller pore size of the composite gel network [203], which can offer better mechanical properties and excellent chemical and thermal stability compared with ionically crosslinked polymer networks [204]. Studies are in progress to develop an enzymatically cross-linkable hydrogel platform with good spatial localization of the encapsulated growth factor and controlled, degradation-dependent release characteristics. ...
In recent years, bone tissue engineering (BTE), as a multidisciplinary field, has shown considerable promise in replacing traditional treatment modalities (i.e., autografts, allografts, and xenografts). Since bone is such a complex and dynamic structure, the construction of bone tissue composite materials has become an attractive strategy to guide bone growth and regeneration. Chitosan and its derivatives have been promising vehicles for BTE owing to their unique physical and chemical properties. With intrinsic physicochemical characteristics and closeness to the extracellular matrix of bones, chitosan-based composite scaffolds have been proved to be a promising candidate for providing successful bone regeneration and defect repair capacity. Advances in chitosan-based scaffolds for BTE have produced efficient and efficacious bio-properties via material structural design and different modifications. Efforts have been put into the modification of chitosan to overcome its limitations, including insolubility in water, faster depolymerization in the body, and blood incompatibility. Herein, we discuss the various modification methods of chitosan that expand its fields of application, which would pave the way for future applied research in biomedical innovation and regenerative medicine.
... In the wound area, inflammation leads to excessive ROS production, which leads to oxidative stress, protein inactivation, cell necrosis, wound infection and a series of phenomena that are not conducive to wound healing, thus leading to the continuous occurrence of inflammation and the formation of chronic wounds and scars [46][47][48]. Therefore, antioxidant dressings can promote wound healing by the effective elimination of excessive ROS, which can reduce oxidative stress, improve wound microenvironment, and cell metabolism, and accelerate wound healing . ...
Injectable Hydrogels with adhesive, antioxidant and hemostatic properties are highly desired for promoting skin injury repair. In this study, we prepared a multi-functional carboxymethyl chitosan/hyaluronic acid-dopamine (CMC/HA-DA) hydrogel, which can be crosslinked by horseradish peroxidase and hydrogen peroxide. The antioxidation, gelation time, degradability, rheology and antihemorrhagic properties of hydrogels can be finely tuned by varying composition ratio. The cytocompatibility test and hemolysis test confirmed that the designed hydrogel holds good biocompatibility. More importantly, the repair effect of the hydrogel on full-thickness skin injury model in mice was studied. The results of wound healing, collagen deposition, immunohistochemistry and immunofluorescence showed that CMC/HA-DA hydrogel could significantly promote angiogenesis and cell proliferation at the injured site. Notably, the inflammatory response can also be regulated to promote the repair of full-thickness skin defect in mice. Results indicate that this injectable CMC/HA-DA hydrogel holds high application prospect for promising wound healing.
... Either by itself [73] or synergistically with horseradish peroxidase (HRP), it could be used in situ to form polymer networks at room temperature [74,75] or to realize 3D printing. When these polymerization schemes were applied to supramolecular hydrogels made from hydrogelators [76], supramolecular peptides [77], or low molecular-weight gelators (LMWGs) [74,78], the resulting hydrogels presented self healing capabilities. When N-hydroxyimide-modified silica NPs were introduced, GOx formed stretchable, tough hydrogel networks at anaerobic conditions and were applicable for bio-scaffold and cell culture [79]. ...
Hydrogels are hydrophilic polymer materials that provide a wide range of physicochemical properties as well as are highly biocompatible. Biomedical researchers are adapting these materials for the ever-increasing range of design options and potential applications in diagnostics and therapeutics. Along with innovative hydrogel polymer backbone developments, designing polymer additives for these backbones has been a major contributor to the field, especially for expanding the functionality spectrum of hydrogels. For the past decade, researchers invented numerous hydrogel functionalities that emerge from the rational incorporation of additives such as nucleic acids, proteins, cells, and inorganic nanomaterials. Cases of successful commercialization of such functional hydrogels are being reported, thus driving more translational research with hydrogels. Among the many hydrogels, here we reviewed recently reported functional hydrogels incorporated with polymer additives. We focused on those that have potential in translational medicine applications which range from diagnostic sensors as well as assay and drug screening to therapeutic actuators as well as drug delivery and implant. We discussed the growing trend of facile point-of-care diagnostics and integrated smart platforms. Additionally, special emphasis was given to emerging bioinformatics functionalities stemming from the information technology field, such as DNA data storage and anti-counterfeiting strategies. We anticipate that these translational purpose-driven polymer additive research studies will continue to advance the field of functional hydrogel engineering.
... The cells are generally seeded on the degradable hydrogels and as they establish the extracellular matrix, the biomaterial gets degraded leaving the renewed tissue with its extracellular matrix (ECM) [102]. Among the tissue engineering applications, hydrogel wound dressing has received great interest as the moist environment provided by the hydrogel supports wound healing and also inhibits wound infection [103]. But, in the case of laccasemediated hydrogels, the in vivo studies performed for wound healing are very few in number and the laccase-based tissue regenerative medicine is yet to be explored thoroughly. ...
The unique physiochemical properties and the porous network architecture of hydrogel seek the attention to be explored in broad range of fields. In the last decade, numerous studies on the development of enzymatically cross-linked hydrogels have been elucidated. Implementing enzyme based cross-linking for fabrication of biomaterials over other crosslinking methods harbor various advantages, especially hydrogels designed using laccase exhibits mild reaction environment, high cross-linking efficiency and less toxicity. To our knowledge this is the first report reviewing the formulation of laccase mediated cross-linking for hydrogel preparation. Here, laccase catalyzed synthesis of hydrogel using polysaccharide viz. arabinoxylan, sugar beet pectin, galactomannan, chitosan etc. and proteins namely soy protein, gelatin, silk fibroin were discussed on highlighting their mechanical properties and its possible field of application. We have summarized the role of phenolic acids in laccase mediated crosslinking particularly ferulic acid which is a component of lignocellulose, serving cell rigidity via crosslinkage. The review also discusses on various biomedical applications such as controlled protein release, tissue engineering, and wound healing. It is anticipated that this review will give a detailed information on different laccase mediated reaction strategies that can be applied for the synthesis of various new biomaterials with tailor made properties.
... This is achieved through the different methods of covalent crosslinking. Hydrogels can be crosslinked via thermal polymerization [33,34], photopolymerization [35][36][37], enzymatic crosslinking [38][39][40], and several other methods [32]. Photopolymerization crosslinking reaction involves a light source that initiates a gel formation. ...
Hydrogels have gained a lot of attention with their widespread use in different industrial applications. The versatility in the synthesis and the nature of the precursor reactants allow for a varying range of hydrogels with different mechanical and rheological properties. Understanding of the rheological behavior and the relationship between the chemical structure and the resulting properties is crucial, and is the focus of this review. Specifically, we include detailed discussion on the correlation between the rheological characteristics of hydrogels and their possible applications. Different rheological tests such as time, temperature and frequency sweep, among others, are described and the results of those tests are reported. The most prevalent applications of hydrogels are also discussed.
... In a mouse study, the application of ointments containing FA and other plant extracts on induced burns modulated the inflammatory response and enhanced wound regeneration [134]. FA-supplemented hydrogels were recently developed to stimulate wound healing and reduce closure time, obtaining favorable outcomes in animal studies [135,136]. ...
The treatment of tissue damage produced by physical, chemical, or mechanical agents involves considerable direct and indirect costs to health care systems. Wound healing involves a series of molecular and cellular events aimed at repairing the defect in tissue integrity. These events can be favored by various natural agents, including the polyphenols in extra virgin olive oil (EVOO). The objective of this study was to review data on the potential effects of different phenolic compounds that can also be found in EVOO on wound healing and closure. Results of in vitro and animal studies demonstrate that polyphenols from different plant species, also present in EVOO, participate in different aspects of wound healing, accelerating this process through their anti-inflammatory, antioxidant, and antimicrobial properties and their stimulation of angiogenic activities required for granulation tissue formation and wound re-epithelialization. These results indicate the potential usefulness of EVOO phenolic compounds for wound treatment, either alone or in combination with other therapies. Human studies are warranted to verify this proposition.
Wound healing presents a complex physiological process that involves a sequence of events orchestrated by various cellular and molecular mechanisms. In recent years, there has been growing interest in leveraging nanomaterials and peptides to enhance wound healing outcomes. Nanocarriers offer unique properties such as high surface area-to-volume ratio, tunable physicochemical characteristics, and the ability to deliver therapeutic agents in a controlled manner. Similarly, peptides, with their diverse biological activities and low immunogenicity, hold great promise as therapeutics in wound healing applications. In this review, authors explore the potential of peptides as bioactive components in wound healing formulations, focusing on their antimicrobial, anti-inflammatory, and pro-regenerative properties. Despite the significant progress made in this field, several challenges remain, including the need for standardized characterization methods, optimization of biocompatibility and safety profiles, and translation from bench to bedside. Furthermore, developing multifunctional nanomaterial-peptide hybrid systems represents promising avenues for future research. Overall, the integration of nanomaterials made up of natural or synthetic polymers with peptide-based formulations holds tremendous therapeutic potential in advancing the field of wound healing and improving clinical outcomes for patients with acute and chronic wounds.
Naturally-derived biomaterials invite immense interest from diverse segments of science and engineering. Recent decades have witnessed a leap in knowledge and efforts in ongoing research with biomaterials as synthons, yet biomaterial research never fails to create surprises. This book summarizes modern knowledge of bioderived materials for beginners in research and advanced readers in materials science.
The book lays the foundations of understanding the design and development of mimetic peptides and enzyme mimetic bioinorganic catalysts, including the toolsets used in the process. Next, the book demonstrates different approaches for obtaining task-specific designer hydrogels. Additional topics covered in the book are tissue engineering and regenerative medicine. From this point, the book presents information on complex biomaterials systems: bacterial cellulose, cell membrane architecture for nanocomposite material design, and whole cellular microorganisms. Chapters provide applied knowledge with information on the strategies used to design novel biomaterials for applications such as drug delivery, therapy and controlled chemical synthesis.
In summary, this book brings together a wealth of information on bioderived materials with versatile applications, derived from different sources, such as plant derivatives and microorganisms (in part or whole as synthons), benefitting readers from multidisciplinary backgrounds.
This state-of-the-art review explores the emerging field of regenerative hydrogels and
their profound impact on the treatment of skin wounds. Regenerative hydrogels, composed mainly
of water-absorbing polymers, have garnered attention in wound healing, particularly for skin
wounds. Their unique properties make them well suited for tissue regeneration. Notable benefits
include excellent water retention, creating a crucially moist wound environment for optimal
healing, and facilitating cell migration, and proliferation. Biocompatibility is a key feature,
minimizing adverse reactions and promoting the natural healing process. Acting as a supportive
scaffold for cell growth, hydrogels mimic the extracellular matrix, aiding the attachment and
proliferation of cells like fibroblasts and keratinocytes. Engineered for controlled drug release,
hydrogels enhance wound healing by promoting angiogenesis, reducing inflammation, and
preventing infection. The demonstrated acceleration of the wound healing process, particularly
beneficial for chronic or impaired healing wounds, adds to their appeal. Easy application and
conformity to various wound shapes make hydrogels practical, including in irregular or challenging
areas. Scar minimization through tissue regeneration is crucial, especially in cosmetic and functional
regions. Hydrogels contribute to pain management by creating a protective barrier, reducing
friction, and fostering a soothing environment. Some hydrogels, with inherent antimicrobial
properties, aid in infection prevention, which is a crucial aspect of successful wound healing. Their
flexibility and ability to conform to wound contours ensure optimal tissue contact, enhancing
overall treatment effectiveness. In summary, regenerative hydrogels present a promising approach
for improving skin wound healing outcomes across diverse clinical scenarios. This review provides
a comprehensive analysis of the benefits, mechanisms, and challenges associated with the use of
regenerative hydrogels in the treatment of skin wounds. In this review, the authors likely delve into
the application of rational design principles to enhance the efficacy and performance of hydrogels
in promoting wound healing. Through an exploration of various methodologies and approaches,
this paper is poised to highlight how these principles have been instrumental in refining the design
of hydrogels, potentially revolutionizing their therapeutic potential in addressing skin wounds. By
synthesizing current knowledge and highlighting potential avenues for future research, this review
aims to contribute to the advancement of regenerative medicine and ultimately improve clinical
outcomes for patients with skin wounds.
Extracellular vesicles have emerged as promising tools in regenerative medicine due to their inherent ability to facilitate intercellular communication and modulate cellular functions. These nanosized vesicles transport bioactive molecules, such as proteins, lipids, and nucleic acids, which can affect the behavior of recipient cells and promote tissue regeneration. However, the therapeutic application of these vesicles is frequently constrained by their rapid clearance from the body and inability to maintain a sustained presence at the injury site. In order to overcome these obstacles, hydrogels have been used as extracellular vesicle delivery vehicles, providing a localized and controlled release system that improves their therapeutic efficacy. This Review will examine the role of extracellular vesicle-loaded hydrogels in tissue regeneration, discussing potential applications, current challenges, and future directions. We will investigate the origins, composition, and characterization techniques of extracellular vesicles, focusing on recent advances in exosome profiling and the role of machine learning in this field. In addition, we will investigate the properties of hydrogels that make them ideal extracellular vesicle carriers. Recent studies utilizing this combination for tissue regeneration will be highlighted, providing a comprehensive overview of the current research landscape and potential future directions.
Hydrogels consist of crosslinked hydrophilic polymers from which their mechanical properties can be modulated for a wide variety of applications. In the last decade, many catechol-based bioin-spired adhesives have been developed following the strategy of incorporating catechol moieties into polymeric backbones. In this work, in order to further investigate the adhesive properties of hydrogels and their potential advantages, several hydrogels based on poly(2-hydroxyethyl methacrylate-co-acrylamide) with N ′ N-methylene-bisacrylamide (MBA), without/with L-3,4-dihydroxyphenylalanine (DOPA) as a catecholic crosslinker, were prepared via free radical copolymerization. 2-Hydroxyethyl methacrylate (HEMA) and acrylamide (AAm) were used as comonomers and MBA and DOPA both as crosslinking agents at 0.1, 0.3, and 0.5 mol.-%, respectively. The polymeric hydrogels were characterized by Fourier transform infrared spectroscopy (FT-IR), thermal analysis and swelling behavior analysis. Subsequently, the mechanical properties of hydrogels were determined. The elastic properties of the hydrogels were quantified using Young's modulus (stress-strain curves). According to the results herein, the hydrogel with a feed monomer ratio of 1:1 at 0.3 mol.-% of MBA and DOPA displayed the highest rigidity and higher failure shear stress (greater adhesive properties). In addition, the fracture lap shear strength of the biomimetic polymeric hydrogel was eight times higher than the initial one (only containing MBA); however at 0.5 mol.-% MBA/DOPA, it was only two times higher. It is understood that when two polymer surfaces are brought into close contact, physical self-bonding (Van der Waals forces) at the interface may occur in an-OH interaction with wet contacting surfaces. The hydrogels with DOPA provided an enhancement in the flexibility compared to unmodified hydrogels, alongside reduced swelling behavior on the biomimetic hydrogels. This approach expands the possible applications of hydrogels as adhesive materials, in wet conditions, within scaffolds that are commonly used as biomaterials in cartilage tissue engineering.
The escalating prevalence of wounds, particularly chronic wounds, poses significant challenges in terms of treatment management and has led to an increase in healthcare expenditure. Hydrogel-based dressings play a crucial role in wound management due to their unique properties. However, there remains a lack of comprehensive reviews on the use of hydrogel-based dressings for wound healing. This review commences with an overview of the process and characteristics of wound healing. Furthermore, we summarize the various functions of hydrogel-based dressings in promoting wound healing, including adhesive property, antibacterial efficacy, hemostasis, angiogenesis promotion, anti-oxidation, anti-inflammatory effect, self-healing, and conductivity. We further discuss the challenges encountered during the healing of different types of wounds, particularly diabetic wounds, and outline the latest advancements in the application of hydrogel-based dressings in the management of different types of wounds. In addition, we conclude and provide an outlook on the application of hydrogel-based dressings in wound healing, with the aim of further enhancing their ability to promote wound healing.
Deciphering the most promising strategy for the evolution of potential wound-healing therapeutics is one of the greatest challenging affairs to date. The development of peptide-based smart scaffolds with innate antimicrobial, anti-inflammatory, and antioxidant properties is an appealing way out. Aligned to the goal a set of Hydrogelators I - IV were developed utilizing the concept of chiral orchestration in diphenylalanine fragment, such that the most potent construct with all the bench marks namely mechanoresponsiveness, biocompatibility, consistent antimicrobial and antioxidant properties, could be fished out from the design. Interestingly, our invitro Antifungal and Lipid peroxidation analysis identified the homochiral isomer (Hydrogelator I), as an ideal candidate for the wound healing experiment. So we proceeded for the invivo measurements in Wister rats. Indeed the wound images demonstrated that with increased recovery time, hydrogelator I displayed a significant reduction in the lesion diameter compared to the marketed drug, and negative control. Even the histopathological measurements using H & E staining demonstrated diminished tissue destruction, neutrophil infiltration necrosis, and lymphatic proliferation in the hydrogelators, incomparison to others, backed by invivo lipid peroxidation data. Overall our investigation certifies hydrogelator I as an effective therapeutic for managing the wound healing complication.
Marine polysaccharides (MPs) are exceptional bioactive materials that possess unique biochemical mechanisms and pharmacological stability, making them ideal for various tissue engineering applications. Certain MPs, including agarose, alginate, carrageenan, chitosan, and glucan have been successfully employed as biological scaffolds in animal studies. As carriers of signaling molecules, scaffolds can enhance the adhesion, growth, and differentiation of somatic cells, thereby significantly improving the tissue regeneration process. However, the biological benefits of pure MPs composite scaffold are limited. Therefore, physical, chemical, enzyme modification and other methods are employed to expand its efficacy. Chemically, the structural properties of MPs scaffolds can be altered through modifications to functional groups or molecular weight reduction, thereby enhancing their biological activities. Physically, MPs hydrogels and sponges emulate the natural extracellular matrix, creating a more conducive environment for tissue repair. The porosity and high permeability of MPs membranes and nanomaterials expedite wound healing. This review explores the distinctive properties and applications of select MPs in tissue regeneration, highlighting their structural versatility and biological applicability. Additionally, we provide a brief overview of common modification strategies employed for MP scaffolds. In conclusion, MPs have significant potential and are expected to be a novel regenerative material for tissue engineering.
Living cells and organisms are composed of numerous biomolecules and control their concentrations and spatial distribution in a spatiotemporal manner to exhibit intricate biological functions. Inspired by the extracellular matrix, synthetic multi-network hydrogels have attracted attention due to their remarkable properties like extremely high toughness. This account summarizes our research progress on one emerging class of the multi-network hydrogels, supramolecular–polymer composite hydrogel. Composite hydrogels can rationally integrate stimulus response of supramolecular gels and stiffness of polymer gels. Super-resolution microscopy visualizes four types of network patterns at the µm scale: an orthogonal and three interactive networks, which may influence the viscoelastic properties of composite hydrogels. We found a kind of composite hydrogel that shows autonomous network remodeling, enabling fracture-induced 3D gel patterning. Furthermore, we demonstrated that supramolecular–polymer composite hydrogels are applicable as a matrix for controlled release of protein biopharmaceuticals in response to antibodies through incorporation of functional molecules such as enzymes and their inhibitors. Supramolecular–polymer composite hydrogels hold promise as the next-generation smart and responsive soft materials for biomedical applications, including tissue engineering and regenerative medicine.
Chiral supramolecular assemblies with helical structures (e. g., proteins with α‐helix, DNA with double helix, collagen with triple‐helix) as the central structure motifs in biological systems play a crucial role in various physiological activities of living organisms. Variations in chiral structure can cause many abnormal physiological activities. To gain insight into the construction, structural transition, and related physiological functions of these complex helix in natural systems, it is necessary to fabricate artificial supramolecular assemblies with controllable helix orientation as research platform. This review discusses recent advances in chiral supramolecular assembly, including the precise construction and regulation of assembled chiral nanostructures with tunable chirality. Chiral structure‐dependent biological activities, including cell proliferation, cell differentiation, antibacterial activity and tissue regeneration, are also discussed. This review not only contributes to further understanding of the importance of chirality in the physiological environment, but also plays an important role in the development of chiral biomedical materials for the treatment of diseases (e. g., tissue engineering regeneration, stem cell transplantation therapy).
Designing wound dressings with inherent multifunctional therapeutic effects is desirable for clinical applications. Herein, a series of multifunctional carboxymethyl chitosan (CMCS)-based hydrogels were fabricated by the facile urate oxidase (UOX)-horseradish peroxidase (HRP) cascade enzymatic crosslinking system. For the first time, the cascade enzymatic crosslinking system was not only used for preparing hydrogel wound dressings but also for accelerating wound healing due to the activity retention of the self-compartmental enzymes. A CMCS derivative (HCMCS-mF) synthesized by successively grafting 4-hydroxybenzaldehyde (H) and 5-methylfurfural (mF) on CMCS and a quaternary ammonium crosslinker (QMal) with terminal grafting maleimide (Mal) groups were combined with enzymatic system for the facile preparation of hydrogels. The mild Diels-Alder (DA) crosslinking reaction between mF and Mal groups constructed the first network of hydrogels. The cascade UOX-HRP system mediated the oxidative crosslinking of phenols thus forming the second gel network. Self-entrapped UOX maintained its enzymatic activity and could continuously catalyze the oxidation of uric acid, generating therapeutic allantoin. These porous, degradable, mechanically stable hydrogels with excellent antioxidant performance and enhanced antibacterial capacity could effectively accelerate skin wound repair by simultaneously reducing oxidative stress, relieving inflammation, promoting collagen deposition and upregulating the expression level of CD31.
In situ hydrogelation of injectable precursors upon biological stimulus is relevant to generate hydrogels under mild conditions and, potentially, at a biological side of interest. Here, it is shown that hydrolytic enzymes can be used to initiate the formation of covalent hydrogel networks, realizing a cleavage‐leading‐to‐gelation strategy. For this purpose, a two‐component system is used, consisting of a 4‐arm polyethylene glycol‐thiodepsipeptide conjugate, PEG4TDP o containing the matrix metalloproteinases MMP‐2‐ and MMP‐9‐cleavable Ac‐Pro‐Leu‐Gly#SLeu‐Leu‐Gly‐ thiodepsipeptide sequence releasing a thiol upon hydrolysis, and a maleimide functionalized 4‐armed PEG (PEG4MAL). PEG4TDP o is synthesized in a PEG‐functionalization protocol involving convergent and divergent synthetic steps without the need for rigorous purification procedures. In a fluorometric assay, it is shown that the construct is in fact cleaved by both investigated MMPs. PEG4TDP o in the presence of 10 wt.% PEG4MAL formed hydrogels upon addition of MMP‐2 or ‐9 with average gelation times of 28 and 40 min, respectively, as is investigated by rheology. The much faster gelation times compared to the enzyme‐free system showed the specific input of the enzymatic reactions. The MMP‐assisted activation and crosslinking strategy can potentially become useful by targeting tissues showing an increased expression of MMPs, such as cancers, or to detect MMPs.
Chronic wounds are a major healthcare challenge owing to their complex healing mechanism and number of impediments to the healing process, like infections, unregulated inflammation, impaired cellular functions, poor angiogenesis, and enhanced protease activity. Current topical care strategies, such as surgical debridement, absorption of exudates, drug-loaded hydrogels for infection and inflammation management, and exogenous supply of growth factors for angiogenesis and cell proliferation, slow the progression of wounds and reduce patient suffering but suffer from low overall cure rates. Therefore, we have developed a proteolytically stable, multifunctional nanoparticle loaded-peptide gel with inherent anti-inflammatory, antibacterial, and pro-angiogenic properties to provide a favorable wound healing milieu by restoring impaired cellular functions. We have fabricated a self-assembled, lauric acid-peptide conjugate gel, LA-LLys-DPhe-LLys-NH2, loaded with yttrium oxide (Y2O3) nanoparticles (NLG). Gel formed a nanofibrous structure, and nanoparticles were passively entrapped within the network. The surface morphology, stability, viscoelastic, and self-healing characteristics of gels were characterized. It showed a high stability against degradation by proteolytic enzymes and highly potent antibacterial activities against E. coli and S. aureus due to the presence of positively charged side chains of lysine in the peptide chain. It also exhibited an excellent antioxidant activity as well as ability to stimulate cell proliferation in murine fibroblast (L929) cells and human umbilical vein endothelial cells (HUVECs). The incorporation of nanoparticles promoted angiogenesis by upregulating pro-angiogenic genes, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF2), and epidermal growth factor (EGFR), and the gel caused complete wound closure in cells. In summary, the Y2O3 nanoparticle-loaded lauric acid-peptide conjugate gel is able to elicit the desired tissue regeneration responses and, therefore, has a strong potential as a matrix for the treatment of chronic wounds.
Chronic wounds are a major healthcare challenge around the world. The presence of bacterial biofilms, accumulation of reactive oxygen species (ROS), and persistent inflammation have been identified as rate-limiting steps in chronic wound healing. Anti-inflammatory drugs, like naproxen (Npx) and indomethacin (Ind), show poor selectivity for the COX-2 enzyme, which plays a key role in producing inflammatory responses. To address these challenges, we have developed conjugates of Npx and Ind with peptides possessing antibacterial, antibiofilm, and antioxidant properties along with enhanced selectivity for the COX-2 enzyme. We have synthesized and characterized peptide conjugates Npx-YYk, Npx-YYr, Ind-YYk, and Ind-YYr, which were self-assembled into supramolecular gels. As envisaged, the conjugates and gels showed high proteolytic stability and selectivity toward the COX-2 enzyme and potent antibacterial activities (>95% within 12 h) against Gram-positive bacteria Staphylococcus aureus, implicated in wound-related infections, eradication of biofilm (∼80%), and radical scavenging (>90%) properties. Cell culture studies with mouse fibroblast cells (L929) and macrophage-like cells (RAW 264.7) showed that gels were cell proliferative in nature (120% viability), which resulted in faster and more efficient scratch healing. Treatment with gels led to a significant decrease in proinflammatory cytokine (TNF-α and IL-6) expressions and an increase in anti-inflammatory gene (IL-10) expression. The gels developed in this work show great promise as a topical agent for chronic wounds or as a coating for medical devices to prevent medical-device-associated infections.
Facile preparation of multifunctional hydrogel wound dressings with inherent versatile properties is highly desirable in practical healthcare. Here, a biocompatible hydrogel was designed and fabricated via mild enzymatic crosslinking and polymerization. We first designed an enzymatic system containing horseradish peroxidase (HRP), H2O2, and the macromolecular initiator—acetoacetyl polyvinyl alcohol (PVA-ACAC), which can generate active PVA-ACAC carbon radicals via HRP-mediated oxidation by H2O2. Trimethylammonium chloride (Q), methacryloyl (MA) and phenol (Ph)-grafted carboxymethyl chitosan (Ph-QCMCS-MA) was then synthesized. HRP catalyzes the oxidation of phenol groups to achieve the fast phenol crosslinking, and PVA-ACAC carbon radicals initiate the polymerization of MA groups simultaneously, finally obtaining the target PPQM gel. The quaternary ammonium and phenol groups endow the PPQM gel with excellent antibacterial and antioxidant properties, respectively. This multifunctional hydrogel, which has additional adhesive and hemostatic properties, could promote wound healing processes in an in vivo full-thickness skin defect experiment by reducing the generation of pro-inflammatory cytokines (IL-6) and upregulating anti-inflammatory factors (IL-10) and angiogenesis-related cytokines (VEGF and α-SMA). As a result, it could be used as competitive wound dressings.
Supramolecular-polymeric hydrogels by combining low-molecular-weight gelators (LMWGs) with polymers have attracted great attention due to their unique double networks. Polymers are generally introduced into an LMWG matrix, thus enhancing the mechanical performance and broadening of the application fields of supramolecular hydrogels. Herein, a series of supramolecular-polymer hydrogels with inherent multiple properties were fabricated as wound dressings. An enzyme-like supramolecular H/G4 hydrogel co-assembled by hemin and guanosine-quartet motifs was successively integrated with hyaluronic acid (HA) and polyaniline (PANI), yielding a supramolecular-polymeric composite hydrogel (namely H/G4-HA(Cu)/PANI). The introduction of Cu2+-crosslinked hydrazide-grafted HA polymeric networks not only enhanced the viscoelasticity of the H/G4 supramolecular hydrogel but also endowed composite hydrogels with bioactive properties as wound healing dressings. The enzyme-like nanofibril H/G4 hydrogel could catalyse the oxidative polymerization of aniline, thus introducing PANI into gel networks. The porous H/G4-HA(Cu)/PANI exhibited a certain degree of swelling ratio under physiological conditions. H/G4-HA(Cu)/PANI also showed degradability, conductivity and appropriate mechanical properties. Through a full-thickness skin defect model of mice, this haemostatic, antioxidant, antibacterial and drug-free H/G4-HA(Cu)/PANI could accelerate wound healing processes by promoting wound closure, collagen deposition and upregulation of the CD31 expression level, which indicates that H/G4-HA(Cu)/PANI could be a promising wound dressing material.
Preventing bacterial infections and accelerating wound closure are essential in the process of wound healing. Current wound dressings lack enough mechanical properties, self-healing ability, and tissue adhesiveness, and the bacterial killing also relies on the use of antibiotic drugs. Herein, a well-designed hybrid hydrogel dressing is constructed by simple copolymerization of acrylamide (AM), 3-acrylamido phenylboronic acid (AAPBA), chitosan (CS), and the nanoscale tannic acid (TA)/ferric ion (Fe3+) complex (TFe). The resulting hydrogel possesses lots of free catechol, phenylboronic acid, amine, and hydroxyl groups and contains many reversible and dynamic bonds such as multiple hydrogen bonds and boronate ester bonds, thereby showing satisfactory mechanical properties, fast self-healing ability, and desirable tissue-adhesive performance. Benefiting from the high photothermal conversion efficiency of the TFe, the hydrogel exhibits satisfactory antibacterial activity against both Gram-positive and Gram-negative bacteria. Moreover, the embedded TFe also endows the hydrogel with good antioxidant activity, anti-inflammatory property, and cell proliferation to promote tissue regeneration. Remarkably, in vivo animal assays reveal that the hybrid hydrogel effectively eliminates biofilm bacteria in the wound sites and accelerates the healing process of infected wounds. Taken together, the developed versatile hydrogels overcome the shortcomings of traditional wound dressings and are expected to become potential antibacterial dressings for future biomedical applications.
Nature-made hydrogels typically combine a wide range of multiscale fibers into biological composite networks, which offer an adaptive property. Inspired by nature, we report a facile approach to construct hybrid hydrogels from a range of natural or commercially available synthetic nongelling polymers (e.g., poly(ethylene glycol), poly(acrylic acid), carboxylated cellulose nanocrystal, and sodium alginate) at a concentration as low as 0.53 wt % using a nonionic fibrous peptide hydrogelator. Through simply mixing the peptide hydrogelator with a polymer aqueous solution, stable hybrid hydrogels can be formed with the concentration of hydrogelator at ∼0.05 wt %. The gel strength of the resulting hydrogels can be effectively modulated by the concentration, molecular weight, and terminal group of the polymer. We further demonstrate that the molecular interactions between the peptide hydrogelator and the polymer are very crucial for the formation of hybrid hydrogel, which synergically induce the gelation at considerably low concentrations. A peptide hydrogelator can be easily obtained by aminolysis of alkyl-oilgo(γ-benzyl-l-glutamate) samples. Live/Dead assays indicate low cytotoxicity of the hybrid hydrogel toward HeLa cells. Combining the low-cost, scalable synthesis, and biocompatibility, the prepared peptide hydrogelator presents a potential candidate to expand the scope of polymer hydrogels for biomedical applications and also shows considerable commercial significance.
Diabetes is a global epidemic that poses a severe challenge to public health. The characteristic features of this disease are hyperglycemia and deterioration of the function of pancreatic β-cells, which leads to oxidative stress and organ damage. Glimepiride is used to treat type II diabetes but is associated with side effects, like lower half-life, faster elimination, and hypoglycemia. Self-assembled peptide gels have drawn attention as a drug delivery depot because of their biocompatibility, diverse design, tunable functionality, and dynamic self-assembly properties. In order to overcome the challenge of oxidative stress and side effects associated with the use of glimepiride, we have developed glimepiride-loaded, self-assembled peptide gels from di- and tripeptides employing amino acids with inherent antioxidant properties. Dipeptides, Fmoc-Tyr-Tyr-NH2 (YY) and Fmoc-Trp-Trp-NH2 (WW), and a tripeptide, Fmoc-Trp-Trp-His-NH2 (WWH), were developed and self-assembled into gels. The gels exhibited excellent viscoelastic properties and self-healing abilities, and the presence of β-sheet secondary structures. The dipeptide gels provided a sustained drug release but more drug was released at physiological pH (7.4) than acidic pH (5 and 6), whereas the tripeptide gel released more drug at acidic pH. The gels showed free radical scavenging activities of more than 90% and were able to decrease the amount of oxidative stress caused by the ROS in HepG2 cells. They were non-toxic to the cell line tested and HepG2 cells treated with the releasate of tripeptide gels showed enhanced glucose uptake. This work for the first time reports the development of glimepiride-loaded self-assembled peptide gels, which can serve as a dynamic, multidimensional biomaterial to reduce oxidative stress, hypoglycemia, and repetitive dosing of drugs in diabetic patients by controlling glimepiride release.
Abstract: Self-assembled structures primarily arise through enzyme-regulated phenomena in nature under persistent conditions. Enzymatic reactions are one of the main biological processes constructing supramolecular hydrogel networks required for biomedical applications. Such enzymatic processes provide a unique opportunity to integrate hydrogel formation. In most cases, the structure and substrates of hydrogels are adjusted by enzyme catalysis due to enzymes’ chemo-, regio- and stereo-selectivity. Such hydrogels processed using various enzyme schemes showed remarkable characteristics as dynamic frames for cells, bioactive molecules, and drugs in tissue engineering, drug delivery, and regenerative medicine. The enzyme-mediated crosslinking hydrogels mimic the extracellular matrices by displaying unique physicochemical properties and functionalities such as water-retention capacity, biodegradability, biocompatibility, biostability, bioactivity, optoelectronic properties, self-healing ability, and shape memory ability. In recent years, many enzymatic systems investigated polymer crosslinking. Herein, we review efficient strategies for enzymatic hydrogelation, including hydrogel synthesis and chemistry, and demonstrate their applicability in biomedical systems. Furthermore, the advantages, challenges, and prospects of enzymatic-crosslinkable hydrogels are discussed. The results of biocompatible hydrogel products show that these crosslinking mechanisms can fulfill requirements for a variety of biomedical applications, including tissue engineering, wound healing, and drug delivery. © 2022, Pleiades Publishing, Ltd.
Ultrasound-initiated thiol-norbornene reaction has been applied to fabricate hydrogels, and the ultrasound conditions in determining the properties of hydrogels have been systematically investigated.
Wound management is a big challenge worldwide, laying a huge financial burden on the government of every nation. Wound dressings that can facilitate wound healing have been under investigation for a long time. Conventional wound dressings, such as bandages, hydrogels and foams, help the wound healing not as efficiently as they were expected since they can’t respond to the wound healing process well. Smart wound dressings that can interact with the wounds, sense and react to the wound condition or environment changing by employing built-in sensors and/or smart materials such as stimuli-responsive materials and self-healing materials, have been proposed to effectively facilitate wound healing. During the past decade, smart wound dressings have sprouted, and various smart wound dressings including biomechanical wound dressing, stimuli-responsive wound dressing, self-healing wound dressing for motional wounds, self-removable wound dressing and monitoring wound dressing have emerged. However, a review on these smart wound dressings is lacking. Thus, in this review, a summary of smart wound dressings will be given, as well as the status, advances, challenges and future trends of this area, aiming to give researchers a clear understanding of the past, present and future of this emerging area.
This study used a new psychrophilic transglutaminase (TGase) to catalyze the formation of protein and peptide hydrogels by forming isopeptide bonds. The psychrophilic recombinant TGase (rTGase) was overexpressed in E. coli and purified using a Ni-Sepharose column followed by stepwise dialysis to recover the cold-active enzyme (specific activity of 1.63 U/mg). The rTGase catalyzed the formation of cold-set hydrogels at 4 °C, which were comprised of high molecular weight gelatin and antioxidant peptides. The antioxidant bioactivity of the cold-set gelatin–peptides composite hydrogels was significantly improved with rTGase at 4 °C for 10 days. To understand the mechanism of the psychrophilic rTGase on the enhanced bioactivity of cross-linked hydrogels, in silico molecular docking studies were performed to assess the binding of antioxidant peptides into the rTGase active pocket, as well as to analyze the interactions of Gln and Lys residues in the antioxidant peptides with amino acid residues in the rTGase catalytic site. The formation of covalent cross-linkages in the gelatin–gelatin, gelatin–peptide and peptide–peptide matrices, and possible structures of composite hydrogels formed by rTGase catalysis in cold conditions, were deduced. The new psychrophilic rTGase enabled stabilization of the antioxidant bioactivity of protein- and peptide-containing cold-set hydrogels formed at low temperatures.
ConspectusEnzymes, a class of highly efficient and specific catalysts in Nature, dictate a myriad of reactions that constitute various cascades in biological systems. There is growing evidence that many cellular reactions within metabolic pathways are catalyzed by matrix-associated multienzyme complexes, not via the free enzymes, verifying the vital effects of microenvironmental organization, which would reveal implications for the high efficiency, specificity, and regulation of metabolic pathways. The extracellular matrix (ECM), as the noncellular component, is composed of various proteins such as collagens, laminins, proteoglycans, and remodeling enzymes, playing the key role in tissue architecture and homeostasis. Hydrogels are defined as highly hydrated polymer materials and maintain structural integrity by physical and chemical force, which are thought of as the most suitable materials for matching the chemical, physical, and mechanical properties with natural ECM. As one specific type of soft and wet materials, hydrogels are suitable three-dimensional carriers to locally confine bioactive guests, such as enzymes, for molecular-level biological interactions. The efficient cascade catalysis can be realized by enzyme-laden hydrogels, which can potentially interact with cells and tissues by material-to-biology communication. In this Account, we present recent progress on the preparation of enzymatic bioactive hydrogels, including in situ coassembly, in situ cross-linking strategy, and in situ enzymatic radical polymerization technology, further promoting their applications on biomedical tissue engineering, biocatalytic health monitoring, and therapeutic research. First, we provide a brief introduction of the basic concept related to an enzymatic strategy in living systems and the importance of bioinspired enzyme-laden bioactive hydrogel systems. We discuss the difficulties of the fabrication of a bioactive hydrogel with a high catalytic efficiency, thereby providing the novel molecular design and regulation based on a noncovalent coassembly and in situ self-immobilization strategy to obtain the compartmentalized enzyme-laden structure. Then the applications of an enzyme-laden bioactive hydrogel for biocatalytic applications are discussed in detail. The enzyme-laden bioactive hydrogel can maintain the favorable perception and regulation behavior of enzymes with optimal enzymatic efficacy between this confined hydrogel network and a surrounding environment. A highlight to the advances in the responsively biocatalytic monitoring and regulation of bioactive hydrogel, including the enzymatic biomedical tissue engineering and health monitoring, enzymatic regulation of tumor reactive oxygen species and therapeutic research are given. Finally, the outlook of open challenges and future developments of this rapidly evolving field is provided. This Account with highlights of diverse enzyme-laden bioactive hydrogel systems not only provides interesting insights to understand the cascade enzymatic strategy of life but also inspires to broaden and enhance the molecular-level material design and bioapplications of existing enzymatic materials in chemistry, materials science, and biology.
Hydrogels with antioxidative and antibacterial properties have emerged as potential dressings for accelerated wound healing. Herein, a series of reduced polydopamine nanoparticles (rPDA NPs) incorporated oxidized dextran/chitosan hybrid hydrogels have been designed for wound healing due to their excellent antioxidative property and antibacterial activity. The physicochemical properties as well as the antioxidative activities of the hydrogels were carefully characterized. The results demonstrated rPDA NPs have better antioxidative activity than the untreated PDA NPs. And the rPDA NPs incorporated oxidized dextran/chitosan hybrid hydrogels had excellent antioxidative properties to protect cells against external oxidative stress. Besides, the hydrogels also showed antibacterial ability to protect the wound against infections. In vitro and in vivo investigations concluded that rPDA NPs incorporated oxidized dextran/chitosan hybrid hydrogels could be served as an effective dressing for accelerated wound healing.
Hydrogels, due to provide a moist environment and mimick the native extracellular matrix (ECM), are of great interest in the field of wound healing. Most developed hydrogels face challenges such as lack of multifunctionality and low mechanical properties, so they cannot properly support skin tissue regeneration. Incorporating various biomaterials and nanostructures into the hydrogels is an emerging approach to develop multifunctional hydrogels with improved or generated new functions that are beneficial for wound healing. These multifunctional hydrogels can be fabricated with a wide range of functions, including antibacterial, antioxidant, bio-adhesiveness, and satisfying mechanical properties. Two approaches are interested in developing multifunctional hydrogel-based dressings; taking the advantages of the chemical composition of biomaterials and addition of nanomaterials or nanostructures. A large number of synthetic and natural polymers, bioactive molecules, or nanomaterials have been used to obtain hydrogel-based dressings with multifunctionality for wound healing applications. In the present review paper, advances in the development of multifunctional hydrogel-based dressings for wound healing have been highlighted.
Currently, the treatment and care of diabetic wounds, which generally possess the characteristics of a high amputation rate, high recurrence rate and high mortality, has developed into a worldwide challenge. Wound dressings have been playing an important role in diabetic wound treatment and keeping innovating to obtain many amazing properties. Among them, hydrogel dressing has become one of the most attractive and promising wound dressings because of its considerable moisture retention, biocompatibility and therapeutic properties. In recent years, with the in-depth understanding of the pathogenesis of diabetic wounds, various functionalized hydrogel dressings have been reported and achieved encouraging results, which has brought great benefits to the improvement of diabetic wounds. In this work, we will systematically and comprehensively summarize the advances of hydrogel dressings in diabetic wounds, aiming to provide not only theoretical support for hydrogel dressing devising but also inspiration for diabetic wound treatment.
Injectable hydrogels can serve as therapeutic vehicles and implants for the treatment of various diseases as well as for tissue repair/regeneration. In particular, the horseradish peroxidase (HRP) and hydrogen peroxide (H2O2)-catalyzed hydrogelation system has attracted much attention, due to its ease of handling and controllable gel properties. In this study, we introduce calcium peroxide (CaO2) as a H2O2-generating reagent to gradually supply a radical source for the HRP-catalyzed crosslinking reaction. This novel therapy can create stiff hydrogels without compromising the cytocompatibility of the hydrogels due to the use of initially high concentrations of H2O2. The physico-chemical properties of the hydrogels can be controlled by varying the concentrations of HRP and CaO2. In addition, the controlled and sustained release of bioactive molecules, including H2O2, O2, and Ca²⁺ ions, from the hydrogels could stimulate the cellular behaviors (attachment, migration, and differentiation) of human mesenchymal stem cells. Moreover, the hydrogels exhibited killing efficacy against both Gram-negative and Gram-positive bacteria, dependent on the H2O2 and Ca²⁺ release amounts. These positive results suggest that hydrogels formed by HRP/CaO2 can be used as potential matrices for a wide range of biomedical applications, such as bone regeneration and infection treatment.
Ferulic acid has low toxicity and possesses many physiological functions (anti-inflammatory, antioxidant, antimicrobial activity, anticancer, and antidiabetic effect). It has been widely used in the pharmaceutical, food, and cosmetics industry. Ferulic acid is a free radical scavenger, but also an inhibitor of enzymes that catalyze free radical generation and an enhancer of scavenger enzyme activity. Ferulic acid has a protective role for the main skin structures: keratinocytes, fibroblasts, collagen, elastin. It inhibits melanogenesis, enhances angiogenesis, and accelerates wound healing. It is widely applied in skin care formulations as a photoprotective agent, delayer of skin photoaging processes, and brightening component. Nonetheless, its use is limited by its tendency to be rapidly oxidized.
Developing injectable antibacterial and conductive shape memory hemostatic with high blood absorption and fast recovery for irregularly shaped and noncompressible hemorrhage remains a challenge. Here we report injectable antibacterial conductive cryogels based on carbon nanotube (CNT) and glycidyl methacrylate functionalized quaternized chitosan for lethal noncompressible hemorrhage hemostasis and wound healing. These cryogels present robust mechanical strength, rapid blood-triggered shape recovery and absorption speed, and high blood uptake capacity. Moreover, cryogels show better blood-clotting ability, higher blood cell and platelet adhesion and activation than gelatin sponge and gauze. Cryogel with 4 mg/mL CNT (QCSG/CNT4) shows better hemostatic capability than gauze and gelatin hemostatic sponge in mouse-liver injury model and mouse-tail amputation model, and better wound healing performance than Tegaderm™ film. Importantly, QCSG/CNT4 presents excellent hemostatic performance in rabbit liver defect lethal noncompressible hemorrhage model and even better hemostatic ability than Combat Gauze in standardized circular liver bleeding model.
Protein-metal ion interactions are ubiquitous in nature and can be utilized for controlling the self-assembly of complex supramolecular architectures and materials. Here, a tunable supramolecular hydrogel is described, obtained by self-assembly of a Zn²⁺-responsive peptide-hyaluronic acid hybrid synthesized using strain promoted click chemistry. Addition of Zn²⁺ triggers folding of the peptides into a helix-loop-helix motif and dimerization into four-helix bundles, resulting in hydrogelation. Removal of the Zn²⁺ by chelators results in rapid hydrogel disassembly. Degradation of the hydrogels can also be time-programed by encapsulation of a hydrolyzing enzyme within the gel, offering multiple possibilities for modulating materials properties and release of encapsulated species. The hydrogel further shows potential antioxidant properties when evaluated using an in vitro model for reactive oxygen species.
A new approach was developed to fabricate tough hybrid hydrogels employing a dual enzyme-mediated redox initiation to achieve post-self-assembly cross-linking polymerization. The resulting hydrogel combined the merits of supramolecular hydrogels with polymeric hydrogels to achieve higher mechanical strength and porous networks. Designed 3D constructs were fabricated via in situ 3D printing. The in situ immobilized GOx/HRP in Gel II exhibited superactivity compared to free enzymes, which might be attributed to the synergistic effect of co-localized GOx and HRP minimizing the distances for mass transport between the gel and the bulk solution. This mechanically strong hybrid hydrogel maintained high reusability and thermal stability as well. In addition, in situ 3D cell culture was demonstrated thus indicating that this biodegradable hybrid hydrogel is biocompatible with cells. The following 3D cell printing further indicates that the hybrid hydrogel is a promising scaffold for bio-related applications such as biocatalysis and tissue engineering.
In the near future, grasses must provide most of the biomass for the production of renewable fuels. However, grass cell walls are characterized by a large quantity of hydroxycinnamic acids such as ferulic and p-coumaric acids, which are thought to reduce the biomass saccharification. Ferulic acid (FA) binds to lignin, polysaccharides and structural proteins of grass cell walls cross-linking these components. A controlled reduction of FA level or of FA cross-linkages in plants of industrial interest can improve the production of cellulosic ethanol. Here, we review the biosynthesis and roles of FA in cell wall architecture and in grass biomass recalcitrance to enzyme hydrolysis.
This communication describes a mild construction of hybrid hydrogels with supramolecular-polymeric networks via a dual enzymatic reaction.
In this study, we investigated the incorporation of multi-component supramolecular hydrogels into agarose hydrogels to create novel hybrid hydrogels. The fracture stresses of the hybrid hydrogels were at least 20 times higher than those of supramolecular hydrogels. The hybrid hydrogels could be fabricated into different shapes, and they allowed other components to be incorporated. We used Congo red as a drug model to study the potential application of hybrid hydrogels as drug delivery carriers, and we used fluorescence microscopy to study the interaction between Congo red and the nanofibers in the hybrid hydrogels. The results indicated that the releasing profile of Congo red strongly interfered with the stability and structures of the supramolecular hydrogels.
Low-molecular-weight gelators (LMWGs)-based supramolecular hydrogels, self-assembled by small molecules via noncovalent interactions, have been recently attracted great attentions due to their unique structure-property relationship and potential applications spanning from functional materials to biomedical devices. Unfortunately, many LMWGs-based supramolecular hydrogels are mechanical weak and can not even be handled by conventional tensile and tearing tests. Here, we propose several design principles to fabricate new LMWG-based hydrogels with a true double-network structure (G4.K+/PDMAAm DN gels), consisting of the supramolecular self-assembly of guanosine, B(OH)3 and KOH as the first, physical G4.K+ network and the covalently cross-linked poly(N, N’-dimethyacrylamide) (PDMAAm) as the second, chemical network. Different from those LMWGs-based supramolecular hydrogels, G4.K+/PDMAAm DN gels exhibit high tensile properties (elastic modulus=0.307 MPa, tensile stress=0.273 MPa, tensile strain=17.62 mm/mm, and work of extension=3.23 MJ/m3) and high toughness (tearing energies=1640 J/m2). Meanwhile, the dynamic, noncovalent bonds in the G4.K+ network can reorganize and reform after being broken, resulting in rapid self-recovery property and excellent fatigue resistance. The stiffness/toughness of G4.K+/PDMAAm DN gels can be recovered by 65%/58% with 1 min resting at room temperature, and the recovery rates are further improved with the increase of temperatures and resting times. Interestingly, G4.K+/PDMAAm DN gels also exhibit UV-triggered luminescence due to the unique G4-quartets structure in G4.K+ supramolecular first network. A new toughening mechanism is proposed to interpret the high strength and toughness of G4.K+/PDMAAm DN gels. We believe that our design principles, along with new G4.K+/PDMAAm DN gel system, will provide a new viewpoint for realizing the tough and strong LMWGs-based gels.
As a promising molecular process for selectively inhibiting cancer cells without inducing acquired drug resistance, enzyme-instructed self-assembly (EISA) usually requires relatively high dosages. Despite its discovery 30 years ago, the translation of the knowledge about NF-B signaling into clinic remains complicated due to the broad roles of NF-B in cellular regulation. Here we show that integrating EISA and NF-B targeting boosts the efficacy of EISA over an order of magnitude without compromising selectivity against cancer cells. That is, in-situ enzymatic self-assembly of a tetrapeptide results in nanofibers, which hardly affect cell viability, but lead to inductive expression of tumor necrosis factor receptor 2 (TNFR2) and decreased expression of three key proteins at the up-stream of NF-B pathway in the cancer cells. Adding the inhibitors targeting NF-B further decreases the expressions of those up-stream proteins, which turns the otherwise innocuous nanofibers to being lethal to the cancer cells, likely causing necroptosis. As the first case of using supramolecular processes to enable synthetic lethality, this work illustrates a versatile approach to translate key regulatory circuits into promising therapeutic targets.
Most of the reported mitochondria targeting molecules are lipophilic and cationic, which may become cytotoxic with accumulation. Here we show enzymatic cleavage of branched peptides that carry negative charges for targeting mitochondria. Conjugating a well-established protein tag (i.e., FLAG-tag) to self-assembling motifs affords the pre-cursors that form micelles. Enzymatic cleavage of the hydrophilic FLAG motif (DDDDK) by enterokinase (ENTK) turns the micelles to nanofibers. After being taken up by cells, the micelles, upon the action of intracellular ENTK, turns into nanofibers to locate mainly at mitochondria. The micelles of the precursors are able to deliver cargos (either small molecules or proteins) into cells, largely to mitochondria and within two hours. Preventing ENTK proteolysis diminishes mitochondria targeting. As the first report of using enzymatic self-assembly for targeting mitochondria and delivery cargos to mitochondria, this work illustrates a fundamentally new way to target subcellular organelles for biomedicine.
We introduce in this study tandem molecular self-assembly of a peptide derivative (compound 1) that is controlled by a combination of enzymatic and chemical reactions. In PBS, compound 1 self-assembles first into nanoparticles by phosphatase and then into nanofibers by glutathione. Liver cancer cells exhibit higher concentrations of both phosphatase and GSH than normal cells. Therefore, the tandem self-assembly of 1 also occurs in liver cancer cell lines HepG2 and QGY7703, in which compound 1 first forms nanoparticles around the cells and then forms nanofibers inside the cells. Compound 1 with this tandem self-assembly property exhibits a large ratio of cellular uptake and inhibition of cell viability between liver cancer cells and normal liver cells. We envision that using both extracellular and intracellular reactions to trigger tandem molecular self-assembly could lead to the development of supramolecular nanomaterials with improved performances in cancer diagnostics and therapy.
Low-molecular-weight gels are currently a hugely important class of materials that are attracting significant interest. These gels are formed when small molecules self-assemble into one-dimensional structures that entangle and cross-link to form a network that is capable of immobilizing the solvent. Here, we critically discuss the current state of the art and highlight two key areas where we believe there is significant untapped potential. The first is the observation that the properties of the gels are highly process dependent, which means that it is possible to access materials with very different properties from a single gelator. Second, using multiple gelators offers the opportunity to prepare materials with a high degree of information content and with a wider range of properties. We aim to spark thought and discussion on these aspects.
A photoactivatable dopamine-conjugated platinum(IV) anticancer complex (Pt-DA) has been incorporated into G-quadruplex G4K⁺ borate hydrogels by using borate ester linkages (Pt-G4K⁺B hydrogel). These were characterized by ¹¹B NMR, attenuated total reflection Fourier transform infrared spectroscopy, circular dichroism, scanning electron microscopy and transmission electron microscopy. Microscopy investigations revealed the transformation of an extended fiber assembly into discrete flakes after incorporation of Pt-DA. Pt-DA showed photocytotoxicity against cisplatin-resistant A2780Cis human ovarian cancer cells (IC50 74 μM, blue light) with a photocytotoxic index <2, whereas Pt-G4K⁺B hydrogels exhibited more potent photocytotoxicity (IC50 3 μM, blue light) with a photocytotoxic index >5. Most notably, Pt-DA and Pt-G4K⁺B hydrogels show selective phototoxicity for cancer cells versus normal fibroblast cells (MRC5).
Tight ligand-receptor binding, paradoxically, is a major root of drug resistance in cancer chemotherapy. To address this problem, instead of using conventional inhibitors or ligands, this paper focuses on the development of a novel process-enzyme-instructed self-assembly (EISA)-to kill cancer cells selectively. Here it is demonstrated that EISA as an intracellular process to generate nanofibrils of short peptides for selectively inhibiting cancer cell proliferation, including drug resistant ones. As the process that turns the non-self-assembling precursors into the self-assembling peptides upon the catalysis of carboxylesterases (CES), EISA occurs intracellularly to selectively inhibit a range of cancer cells that exhibit relatively high CES activities. More importantly, EISA inhibits drug resistant cancer cells (e.g., triple negative breast cancer cells (HCC1937) and platinum-resistant ovarian cells (SKOV3, A2780cis)). With the IC50 values of 28-80 and 25-44 µg mL(-1) of l- and d-dipeptide precursors against cancer cells, respectively, EISA is innocuous to normal cells. Moreover, using coculture of cancer and normal cells, the selectivity of EISA is validated against cancer cells. Besides revealing that intracellular EISA cause apoptosis or necroptosis to kill the cancer cells, this work illustrates a new approach to amplify the enzymatic difference between cancer and normal cells and to expand the pool of drug candidates for potentially overcoming drug resistance in cancer therapy.
Statement of significance:
In this report, we have shown the following significance supported by the experimental results. 1, we successfully developed, characterized and screened a novel pH-responsive peptide 2, we successfully developed a novel and biocompatible pH-sensitive peptide hydrogel as glucose-responsive insulin delivery system loaded with glucose oxidase, catalase and insulin. 3, we successfully confirmed that the hydrogel platform could regulate the blood glucose level in vitro and in vivo. Overall, we have shown enough significance and novelty with this smart hydrogel platform in terms of biomaterials, peptide chemistry, self-assembly, hydrogel and drug delivery. So we believe this manuscript is suitable for Acta Biomaterialia.
Hybrid hydrogels based on a guanidinium-containing oligopeptide are prepared via two dual-enzyme-triggered and simultaneous processes - self-assembly and polymerization. Furthermore, an extended time window is available for in situ viscosity-controlled 3D printing. In vivo hemostatic experiments elucidate that this guanidinium-containing hydrogel can accelerate the hemostasis process.
Carboxymethylpullulan (CMP) has been modified in a two-step grafting reaction of ferulic acid (FA). Acid adipic dihydrazyde (ADH) was first reacted with FA activated with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). Then the product of this first reaction was reacted with CMP (activated with EDC). Grafted polysaccharides structure was confirmed by FTIR and 1H NMR spectroscopy. Analyses by size-exclusion chromatography (SEC) coupling on-line with a multi-angle light scattering detector (MALS), a viscometer and a differential refractive index detector (DRI) (SEC/MALS/DRI/Visco) showed that associations between FA moieties occurred due to hydrophobic interactions. The grafting rates of FA were determined by the Folin-Ciocalteu method and were found between 1.0% and 11.2% (mol/mol anhydroglucose unit). The CMP-FA were then enzymatically cross-linked with laccase from Pleurotus ostreatus. The crosslinking reactions were followed by rheological measurements, demonstrating the influence of laccase concentration on kinetics. Elastic modulus and swelling rates of hydrogels depends on FA content only for low values.
Polyacrylamide hydrogels were prepared using molecular hydrogels composed of a low-molecular-weight gelator system, octylaldonamide/sodium dodecyl sulfate as templates by photopolymerization, and the effect of the template on the polymer hydrogel network was examined on the basis of the polymer hydrogels' performance in compression tests. It was found that the crushing stress of the obtained polymer hydrogels was enhanced by using the molecular gel templates. This journal is
Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug-resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme-instructed self-assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug-resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre-installed on the precursors to form the peptides that self-assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug-resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non-cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects.
Combining low molecular weight gelators (LMWGs) with polymers is a broad yet relatively recent field, in a phase of rapid expansion and with huge potential for exploitation. This review provides an overview of the state-of-the-art and reflects on new technologies that might be unlocked. We divide LMWG–polymer systems into five categories: (i) polymerisation of self-assembled LMWG fibres, (ii) capture of LMWG fibres in a polymer matrix, (iii) addition of non-gelling polymer solutions to LMWGs, (iv) systems with directed interactions between polymers and LMWGs, and (v) hybrid gels containing both LMWGs and polymer gels (PGs). Polymers can have significant impacts on the nanoscale morphology and materials performance of LMWGs, and conversely LMWGs can have a major effect on the rheological properties of polymers. By combining different types of gelation system, it is possible to harness the advantages of both LMWGs and PGs, whilst avoiding their drawbacks. Combining LMWG and polymer technologies enhances materials performance which is useful in traditional applications, but it may also yield major steps forward in high-tech areas including environmental remediation, drug delivery, microfluidics and tissue engineering.
Supramolecular hydrogels derived from natural products have promising applications in diagnostics, drug delivery and tissue engineering. We studied formation of a long-lived hydrogel made by mixing guanosine (G 1) with 0.5 equiv of KB(OH)4. This ratio of borate anion to ligand is crucial for gelation as it links two molecules of G 1, which facilitates cation-templated assembly of G4•K+-quartets. The guanosine-borate (GB) hydrogel, characterized by cryo-TEM, CD and 11B MAS NMR, is stable in water that contains physio-logically relevant concentrations of K+. Further, non-covalent interactions, such as electrostatics and π-stacking and hy-drogen bonding, enable incorporation of a cationic dye and nucleosides into the GB hydrogel.
A simple approach to a patterned multidomain gel is reported, combining a pH-responsive low-molecular-weight gelator (LMWG) and a photoinducible polymer gelator (PG). Using SEM (scanning electron microscopy), NMR spectroscopy, and CD, we demonstrate that self-assembly of the LMWG network occurs in the presence of the PG network, but that the PG has an influence on LMWG assembly kinetics and morphology. The application of a mask during photoirradiation allows patterning of the PG network; we define the resulting system as a "multidomain gel"-one domain consists of a LMWG, whereas the patterned region contains both LMWG and PG networks. The different domains have different properties with regard to diffusion of small molecules, and both gelator networks can control diffusion rates to give systems capable of controlled release. Such materials may have future applications in multikinetic control of drug release, or as patterned scaffolds for directed tissue engineering.
We report a novel gelator functionalised with hydrazides (as replacements for carboxylic acids) which, as a result, is able to assemble into hydrogels across a wide pH range - this gelator exhibits pH-switchable dye adsorption-desorption dependent on protonation of the target dyes and their resulting interactions with the self-assembled gel nanofibres.
The effect of polymeric additives on molecular gelation was explored using poly(acrylic acid) and pyridine-based gelators. A significant reduction in the critical gel concentration (cgc) and an increase in gel strength were observed when the polymer was present during gel formation. Detailed studies revealed that the polymer is adsorbing onto the growing fibers, reducing the growth rates, and leading to thinner fibers. These and other morphological changes lead to improved gel properties by increasing the number of fiber–fiber entanglements. Several other polymers were briefly examined and these studies revealed that polymer structure is important. The polymer containing a complementary functional group relative to the gelator (e.g., H-bond donor/acceptor) provided the lowest cgc.
The development of smart biomaterials for tissue regeneration has become the focus of intense research interest. More opportunities are available by the composite approach of combining the biomaterials in the form of biopolymers and/or bioceramics either synthetic or natural. Strategies to provide smart capabilities to the composite biomaterials primarily seek to achieve matrices that are instructive/inductive to cells, or that stimulate/trigger target cell responses that are crucial in the tissue regeneration processes. Here, we review in-depth, recent developments concerning smart composite biomaterials available for delivery systems of biofactors and cells and scaffolding matrices in tissue engineering. Smart composite designs are possible by modulating the bulk and surface properties that mimic the native tissues, either in chemical (extracellular matrix molecules) or in physical properties (e.g. stiffness), or by introducing external therapeutic molecules (drugs, proteins and genes) within the structure in a way that allows sustainable and controllable delivery, even time-dependent and sequential delivery of multiple biofactors. Responsiveness to internal or external stimuli, including pH, temperature, ionic strength, and magnetism, is another promising means to improve the multifunctionality in smart scaffolds with on-demand delivery potential. These approaches will provide the next-generation platforms for designing three-dimensional matrices and delivery systems for tissue regenerative applications.
Hydrogels are high-water content materials prepared from cross-linked polymers that are able to provide sustained, local delivery of a variety of therapeutic agents. Use of the natural polymer, chitosan, as the scaffold material in hydrogels has been highly pursued thanks to the polymer's biocompatibility, low toxicity, and biodegradability. The advanced development of chitosan hydrogels has led to new drug delivery systems that release their payloads under varying environmental stimuli. In addition, thermosensitive hydrogel variants have been developed to form a chitosan hydrogel in situ, precluding the need for surgical implantation. The development of these intelligent drug delivery devices requires a foundation in the chemical and physical characteristics of chitosan-based hydrogels, as well as the therapeutics to be delivered. In this review, we investigate the newest developments in chitosan hydrogel preparation and define the design parameters in the development of physically and chemically cross-linked hydrogels.
By covalently connecting taxol with a motif that is prone to self-assemble, we successfully generate the precursor (5a), the hydrogelator (5b), and hydrogel of a taxol derivative without compromising the cytotoxic activity of the taxol. This approach promises a general method to create nanofibers of therapeutic molecules that have a dual role, as both the delivery vehicle and the drug itself.
Biocompatible hydrogels have a wide variety of potential applications in biotechnology and medicine, such as the controlled delivery and release of cells, cosmetics and drugs, and as supports for cell growth and tissue engineering. Rational peptide design and engineering are emerging as promising new routes to such functional biomaterials. Here, we present the first examples of rationally designed and fully characterized self-assembling hydrogels based on standard linear peptides with purely alpha-helical structures, which we call hydrogelating self-assembling fibres (hSAFs). These form spanning networks of alpha-helical fibrils that interact to give self-supporting physical hydrogels of >99% water content. The peptide sequences can be engineered to alter the underlying mechanism of gelation and, consequently, the hydrogel properties. Interestingly, for example, those with hydrogen-bonded networks of fibrils melt on heating, whereas those formed through hydrophobic fibril-fibril interactions strengthen when warmed. The hSAFs are dual-peptide systems that gel only on mixing, which gives tight control over assembly. These properties raise possibilities for using the hSAFs as substrates in cell culture. We have tested this in comparison with the widely used Matrigel substrate, and demonstrate that, like Matrigel, hSAFs support both growth and differentiation of rat adrenal pheochromocytoma cells for sustained periods in culture.
Low-molecular-weight gelators form supramolecular gels in organic fluids, aqueous solutions and both organic and aqueous solutions through supramolecular interactions such as hydrogen-bonding, van der Waals, hydrophobic, pi-stacking, coordination, donor-acceptor and charge-transfer interactions. Molecules having chirality, especially, L-amino acids, are often used as a platform of low-molecular-weight gelators. This tutorial review highlights recent and current advances in low-molecular-weight gelators based on L-lysine. L-lysine based gelators are prepared through easy synthetic procedures, and some classes of gelators are synthesized by the introduction of various functional groups. In this review, the synthesis of organogelators, hydrogelators and amphiphilic gelators and their gelation properties are discussed.