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Bioinspired pH- and Temperature-Responsive Injectable Adhesive Hydrogels with Polyplexes Promotes Skin Wound Healing
Abstract
Despite great potential, the delivery of genetic materials into cells or tissues of interest remains challenging owing to their susceptibility to nuclease degradation, lack of permeability to the cell membrane, and short in vivo half-life, which severely restrict their widespread use in therapeutics. To surmount these shortcomings, we developed a bioinspired in situ-forming pH- and temperature-sensitive injectable hydrogel depot that could control the delivery of DNA-bearing polyplexes for versatile biomedical applications. A series of multiblock copolymer, comprised of water soluble poly(ethylene glycol) (PEG) and pH- and temperature-responsive poly(sulfamethazine ester urethane) (PSMEU), has been synthesized as in situ-forming injectable hydrogelators. The free-flowing PEG-PSMEU copolymer sols at high pH and room temperature (pH 8.5, 23 oC) were transformed to stable gel at the body condition (pH 7.4, 37 oC). Physical and mechanical properties of hydrogels, including their degradation rate and viscosity, are elegantly controlled by varying the composition of urethane ester units. Subcutaneous administration of free-flowing PEG-PSMEU copolymer sols to the dorsal region of Sprague-Dawley rats instantly formed hydrogel depot. The degradation of the hydrogel depot was slow at the beginning and found to be bioresorbable after two months. Cationic protein or DNA-bearing polyplex-loaded PEG-PSMEU copolymer sols formed stable gel and controlled its release over 10 days in vivo. Owing to the presence of urethane linkages, the PEG-PSMEU possesses excellent adhesion strength to wide range of surfaces including glass, plastic and fresh organs. More importantly, the hydrogels effectively adhered on human skin and peeled easily without eliciting an inflammatory response. Subcutaneous implantation of PEG-PSMEU copolymer sols effectively sealed the ruptured skin, which accelerated the wound healing process as observed by the skin appendage morphogenesis. The bioinspired in situ-forming pH- and temperature-sensitive injectable adhesive hydrogel may provide a promising platform for myriad biomedical applications as controlled delivery vehicle, adhesive and tissue regeneration.
... In addition, the functionalized CS lowered the gelation point to 32 • C, near the physiological value. The in vivo study showed that the thermosensitive hydrogel properly seals the wound area and promotesaccelerated healing [72]. Because thermo-responsive hydrogels behavior only lies on the amphiphilic properties of the polymers' backbones, these formulations are considered non-toxic, cost-effective, and easy obtained. ...
... DNA-bearing polyplexes were included in the copolymer solution and the controlled released from the 3D matrix formed in situ was assessed. Moreover, the hydrogel showed excellent adhesive properties and was easy to remove from the affected skin, being suitable for wound healing treatment [72]. ...
Wound management represents a well-known continuous challenge and concern of the global healthcare systems worldwide. The challenge is on the one hand related to the accurate diagnosis, and on the other hand to establishing an effective treatment plan and choosing appropriate wound care products in order to maximize the healing outcome and minimize the financial cost. The market of wound dressings is a dynamic field which grows and evolves continuously as a result of extensive research on developing versatile formulations with innovative properties. Hydrogels are one of the most attractive wound care products which, in many aspects, are considered ideal for wound treatment and are widely exploited for extension of their advantages in healing process. Smart hydrogels (SHs) offer the opportunities of the modulation physico-chemical properties of hydrogels in response to external stimuli (light, pressure, pH variations, magnetic/electric field, etc.) in order to achieve innovative behavior of their three-dimensional matrix (gel–sol transitions, self-healing and self-adapting abilities, controlled release of drugs). The SHs response to different triggers depends on their composition, cross-linking method, and manufacturing process approach. Both native or functionalized natural and synthetic polymers may be used to develop stimuli-responsive matrices, while the mandatory characteristics of hydrogels (biocompatibility, water permeability, bioadhesion) are preserved. In this review, we briefly present the physiopathology and healing mechanisms of chronic wounds, as well as current therapeutic approaches. The rational of using traditional hydrogels and SHs in wound healing, as well as the current research directions for developing SHs with innovative features, are addressed and discussed along with their limitations and perspectives in industrial-scale manufacturing.
... These gels are widely used because they can be dissolved at room temperature (25°C) and turned into a gel by injecting them into the body and reaching the temperature of the material to about 37°C (Nguyen et al., 2019). The gelation mechanism in this category of materials is that the hydrogen bond between the side groups of monomers and water in the solution weakens with increasing temperature, and gelation and contraction occur with the strength of hydrophobic interactions of the main chain, and the dehydrated polymer is formed (Figure 1) (Le et al., 2018). PNIPAM Poly (N-isopropyl acrylamide) is the most famous member of this family with an LCST of about 32°C, and its shrinking behavior occurs with a state transition from the extended helix to the coiledcoil. ...
... iii) The hydrogels' tissue adhesion properties are used in wound healing to close wounds and restore tissue structure and function. Reprinted with permission from (Le et al., 2018). Copyright 2018 American Chemical Society. ...
Hydrogels are widely used biomaterials in the delivery of therapeutic agents, including drugs, genes, proteins, etc., as well as tissue engineering, due to obvious properties such as biocompatibility and their similarity to natural body tissues. Some of these substances have the feature of injectability, which means that the substance is injected into the desired place in the solution state and then turns into the gel, which makes it possible to administer them from a way with a minimal amount of invasion and eliminate the need for surgery to implant pre-formed materials. Gelation can be caused by a stimulus and/or spontaneously. Suppose this induces due to the effect of one or many stimuli. In that case, the material in question is called stimuli-responsive because it responds to the surrounding conditions. In this context, we introduce the different stimuli that cause gelation and investigate the different mechanisms of the transformation of the solution into the gel in them. Also, we study special structures, such as nano gels or nanocomposite gels.
... Due to their unique properties, hydrogels have been widely used in a number of applications including drug delivery, tissue engineering, and regenerative medicine. Based on their crosslinking mechanisms, hydrogels can be classified into physically crosslinked and chemically crosslinked hydrogels [5][6][7][8][9]. Physically crosslinked hydrogels are generally prepared through physical interactions, such as hydrophobic interactions, static electronic interactions, hydrogen bondings, etc. ...
... 25 No gelation No gelation 10 min 5 min DA-GLT0. 5 No gelation 10 min 1 min <5 s DA-GLT0. 75 No gelation 5min <5 s <5 s ...
In this study, a series of gelatin/silver nanoparticles (AgNPs) composite hydrogels are prepared for the first time through the facile in situ formation of AgNPs. AgNPs, which are formed by reducing Ag+ using dopamine-conjugated gelatins. These can simultaneously crosslink gelatin molecules, thus generating three-dimentional and porous hydrogels. The gelation time and pore sizes of these composite hydrogels can be controlled by controlling the feeding concentration of AgNO3 and weight content of gelatin in water, respectively. The feeding concentration of AgNO3 also has an effect on the equilibrium swelling ratio of the hydrogels. Moreover, these composite hydrogels, with a controllable gelation time and in situ forming ability, exhibit good adhesive properties and can be used as drug-release depots.
... Polymeric injectable hydrogels have emerged as captivating subjects of research in the biomedical field owing to their distinctive properties, including tunability, mechanical flexibility, and most notably, their ability to be injected with low invasiveness for patient implantation [3][4][5][6]. Most injectable hydrogels have been developed, as described in the literature, by employing external stimuli such as temperature via physical crosslinking methods [7][8][9][10]. Injectable hydrogels can be developed using different types of polymers such as natural and synthetic polymers in different ways and are employed in the biomedical field [11,12]. ...
Injectable hydrogels offer numerous advantages in various areas, which include tissue engineering and drug delivery because of their unique properties such as tunability, excellent carrier properties, and biocompatibility. These hydrogels can be administered with minimal invasiveness. In this study, we synthesized an injectable hydrogel by rehydrating lyophilized mixtures of guar adamantane (Guar-ADI) and poly-β-cyclodextrin (p-βCD) in a solution of phosphate-buffered saline (PBS) maintained at pH 7.4. The hydrogel was formed via host-guest interaction between modified guar (Guar-ADI), obtained by reacting guar gum with 1-adamantyl isocyanate (ADI) and p-βCD. Comprehensive characterization of all synthesized materials, including the hydrogel, was performed using nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and rheology. The in vitro drug release study demonstrated the hydrogel’s efficacy in controlled drug delivery, exemplified by the release of bovine serum albumin (BSA) and anastrozole, both of which followed first-order kinetics. Furthermore, the hydrogel displayed excellent biocompatibility and served as an ideal scaffold for promoting the growth of mouse osteoblastic MC3T3 cells as evidenced by the in vitro biocompatibility study.
... [9] Hydrogels are excellent for biomedical applications because they allow the drug to be easily encapsulated, distributed evenly into non-uniform shaped spots, and persist at specific sites. [115,116] The physically crosslinked CS/PVP hydrogels demonstrated a controlled and sustained drug release. In this regard, Su et al. employed CS/RO-PVP hydrogels for the DDS using an alendronate sodium model drug. ...
Chitosan (CS) and poly(vinyl pyrrolidone) (PVP) blend provide enhanced mechanical properties, biocompatibility, stability, antimicrobial properties, and versatility in fabrication. Due to these inherent biocompatible and antimicrobial properties, CS/PVP based hydrogels have been used in various biomedical applications. Herein, we have provided an overview of the recent developments in the fabrication of CS/PVP hydrogels and their nanocomposite with better structural and functional properties. Combining CS/PVP with nano-architectures results in amendments in the structure and properties of the CS/PVP matrices. Hence, recent developments in using CS/PVP hydrogels and their nanocomposites for drug delivery, protein/gene delivery, and wound healing applications are described here. ARTICLE HISTORY
... In general, the actions of different stimulating factors will cause hydrogels to undergo reversible or irreversible changes in their chemical structures and physical properties [22], such as degradation, shrinking or swelling, sol-gel transition, competitive binding, and self-assembly [29]. Smart responsive-hydrogels with unique features are being developed for use in controlled drug delivery [24,32,33], tissue engineering [34,35], biosensors [14,36], wound dressing [37][38][39], and cancer treatment [40,41]. ...
Bone and cartilage regeneration is an area of tremendous interest and need in health care. Tissue engineering is a potential strategy for repairing and regenerating bone and cartilage defects. Hydrogels are among the most attractive biomaterials in bone and cartilage tissue engineering, mainly due to their moderate biocompatibility, hydrophilicity, and 3D network structure. Stimuli-responsive hydrogels have been a hot topic in recent decades. They can respond to external or internal stimulation and are used in the controlled delivery of drugs and tissue engineering. This review summarizes current progress in the use of stimuli-responsive hydrogels in bone and cartilage regeneration. The challenges, disadvantages, and future applications of stimuli-responsive hydrogels are briefly described.
... To end this, many researchers have focused on the development of biomimetic materials for promoting tissue regeneration and wound healing, which can be regarded as an important regulator to promote cell proliferation and differentiation in this landscape over the past few decades. For instance, natural and synthetic materials have been designed for wound healing by rapid advances in biomedical science and technology, including hydrogels, electrospun nanofiber, sponges, films, and powder [5][6][7][8][9][10][11][12]. Among these, hydrogels are the most promising and attractive materials for wound dressing due to good biocompatibility, natural drug-loading structure, and similarity to extracellular matrix (ECM) [13][14][15][16]. ...
Development of biomimetic hydrogel-based wound healing is highly desirable for addressing life-threatening infectious skin injuries but has proved to be extremely challenging. However, poor tissue adhesive performance, stretchability and difficult fixation lead to conventional wound dressings failing to adapt to dynamic wounds with high-frequency movement or special fluctuant positions. Herein, we present a new biomimetic natural-synthetical combination by integrating Osteichthyes-extracted gelatins into hydrophilic polymeric networks to form unique tough, adhesive, self-healable composite hydrogels. The resultant Gelatin/PHEAA hydrogel without any growth factors/fungicides has high mechanical strength (∼1.0 MPa), high interfacial toughness (>1000 J/m²), and remarkable antifouling activity, enabling the hydrogel to effectively inhibit bacterial proliferation and promote the wound healing. Moreover, due to the abundant hydrogen bonds in composite crosslinked networks, the Gelatin/PHEAA hydrogels maintain high, repeatable adhesion even in high dynamic cases, regardless of wet or dry environments and the types of solid nonporous substrates. Further in vitro and in vivo full-thickness skin incision model confirms that the Osteichthyes-extracted proteins can accelerate collagen deposition and vascular regeneration, leading to a faster wound closure efficiency. Ultimately, we believe that the designed tough Gelatin/PHEAA hydrogels can be high-value candidates for managing rapid wound healing, while the proposed structural biomimetic combination can inspire researchers to design more interesting and effective biomaterials for clinical translation and health care.
... This in situ storage form is suitable for the delivery and transfection of nucleic acids. Le et al. formed a hydrogel reservoir via subcutaneous injection of PEG-modified poly(sulfamethazine ester urethane) sol on the dorsal side of Sprague Dawley rats and observed that the hydrogel reservoir could be effectively released in situ for more than 2 months [178]. Skin, the largest immune organ of the human body, induces an immune response equivalent to that of other vaccination methods efficiently with a relatively low dose, making it an ideal vaccination site. ...
Nucleic acid vaccines, especially messenger RNA (mRNA) vaccines, display unique benefits in the current COVID-19 pandemic. The application of polymeric materials as delivery carriers has greatly promoted nucleic acid vaccine as a promising prophylactic and therapeutic strategy. The inherent properties of polymeric materials render nucleic acid vaccines with excellent in vivo stability, enhanced biosafety, specific cellular uptake, endolysosomal escape, and promoted antigen expression. Although polymeric delivery of nucleic acid vaccines has progressed significantly in the past decades, clinical translation of polymer-gene vaccine systems still faces insurmountable challenges. This review summarizes the diverse polymers and their characterizations and representative formulations for nucleic acid vaccine delivery. We also discussed existing problems, coping strategies, and prospect relevant to applications of nucleic acid vaccines and polymeric carriers. This review highlights the rational design and development of polymeric vaccine delivery systems towards meeting the goals of defending serious or emerging diseases.
... Electrical signal-responsive hydrogels endure swelling and contracting when subjected to an electric field. The demerit of some systems is that due to the charge orientation, one side swells while the other contracts, thus, comprising the stability [28]. Polyelectrolytes, such as poly(2-acrylamido-2-methylpropane sulphonic acid-co-n-butlymethacrylate), are usually employed to formulate these systems [29,30]. ...
Gels are semisolid, homogeneous systems with continuous or discrete therapeutic molecules in a suitable lipophilic or hydrophilic three-dimensional network base. Innovative gel systems possess multipurpose applications in cosmetics, food, pharmaceuticals, biotechnology, and so forth. Formulating a gel-based delivery system is simple and the delivery system enables the release of loaded therapeutic molecules. Furthermore, it facilitates the delivery of molecules via various routes as these gel-based systems offer proximal surface contact between a loaded therapeutic molecule and an absorption site. In the past decade, researchers have potentially explored and established a significant understanding of gel-based delivery systems for drug delivery. Subsequently, they have enabled the prospects of developing novel gel-based systems that illicit drug release by specific biological or external stimuli, such as temperature, pH, enzymes, ultrasound, antigens, etc. These systems are considered smart gels for their broad applications. This review reflects the significant role of advanced gel-based delivery systems for various therapeutic benefits. This detailed discussion is focused on strategies for the formulation of different novel gel-based systems, as well as it highlights the current research trends of these systems and patented technologies.
... An intelligent drug delivery system can release an active chemical at the proper place and at a rate that adjusts in response to disease progression [127].Some of the multi-responsive bioadhesives and their applications are provided in Table 6. Le et al. [128] synthesized pH and temperature-sensitive injectable bioadhesives of poly (sulfamethazine-ester-urethane) (PSMEU) and poly(ethylene glycol) (PEG) by in-situ developing injectable hydrogelators ( Figure 7A). Although PEG-PSMEU bioadhesive was free-flowing at ambient temperature, it quickly became a gel when exposed to body physiological conditions (pH 7.4 and 37 • C). ...
With the advent of “intelligent” materials, the design of smart bioadhesives responding to chemical, physical, or biological stimuli has been widely developed in biomedical applications to minimize the risk of wounds reopening, chronic pain, and inflammation. Intelligent bioadhesives are free-flowing liquid solutions passing through a phase shift in the physiological environment due to stimuli such as light, temperature, pH, and electric field. They possess great merits, such as ease to access and the ability to sustained release as well as the spatial transfer of a biomolecule with reduced side effects. Tissue engineering, wound healing, drug delivery, regenerative biomedicine, cancer therapy, and other fields have benefited from smart bioadhesives. Recently, many disciplinary attempts have been performed to promote the functionality of smart bioadhesives and discover innovative compositions. However, according to our knowledge, the development of multifunctional bioadhesives for various biomedical applications has not been adequately explored. This review aims to summarize the most recent cutting-edge strategies (years 2015–2021) developed for stimuli-sensitive bioadhesives responding to external stimuli. We first focus on five primary categories of stimuli-responsive bioadhesive systems (pH, thermal, light, electric field, and biomolecules), their properties, and limitations. Following the introduction of principal criteria for smart bioadhesives, their performances are discussed, and certain smart polymeric materials employed in their creation in 2015 are studied. Finally, advantages, disadvantages, and future directions regarding smart bioadhesives for biomedical applications are surveyed.
... Despite advancements in treatment options, including surgery, chemotherapy, and radiotherapy, the prognosis of patients with cancer remains poor because of the clinically elusive nature of the disease [1]. In addition, off-target effects in normal tissues remain a major safety concern [2,3]. As conventional cancer treatment options remain insufficient, the development of new therapeutic approaches, such as oncolytic virotherapy, are under active investigation [4]. ...
Oncolytic adenovirus (oAd) elicits antitumor activity by preferential viral replication in cancer cells. However, poor systemic administrability or suboptimal intratumoral retainment of the virus remains a major challenge toward maximizing the antitumor activity of oAd in a clinical environment. To surmount these issues, a variety of non-immunogenic polymers has been used to modify the surface of oAds chemically or physically. Complexation of oAd with polymers can effectively evade the host immune response and reduces nonspecific liver sequestration. The tumor-specific delivery of these complexes can be further improved upon by inclusion of tumor-targeting moieties on the surface. Therefore, modification of the Ad surface using polymers is viewed as a potential strategy to enhance the delivery of Ad via systemic administration. This review aims to provide a comprehensive overview of polymer-complexed Ads, their progress, and future challenges in cancer treatment.
... Thus far, numerous viral vectors, including lentivirus, adenovirus (Ad), adeno-associated virus, and retrovirus, have often been used as viral gene delivery systems [5,9]. Among them, Ad is a promising candidate and extensively investigated in viral-based gene therapy owing to its high gene delivery efficacy, no risk of insertional mutagenesis, and facile production of viral vectors at high titers [10][11][12]. Owing to these features, viral gene delivery vectors received attention in gene delivery [13]. ...
Adenoviruses (Ads) are attractive nonviral vectors and show great potential in cancer gene therapy. However, inherent properties of Ads, including immunogenicity, nonspecific toxicity, and coxsackie and adenovirus receptor (CAR)-dependent cell uptake, limit their clinical use. To surmount these issues, we developed a pH- and glutathione-responsive poly(ethylene glycol)-poly(ꞵ-aminoester)-polyethyleneimine (PPA) for conjugation with Ad. The pH sensitivity of the PPA copolymer was elegantly tuned by substitution with different amino acids (arginine, histidine, and tryptophan), piperazines (Pip1, Pip2, and Pip3), and guanidine residues in the backbone of the PPA conjugate. PPA copolymer was further functionalized with short-chain cross-linker succinimidyl 3-(2-pyridyldithio)propionate) (SPDP) to obtain PPA-SPDP for facile conjugation with Ad. The PPA-conjugated Ad (PPA-Ad) conjugate was obtained by reacting PPA-SPDP conjugate with thiolated Ad (Ad-SH). Ad-SH was prepared by reacting Ad with 2-iminothiolane. The size distribution and zeta potential results of PPA-Ad conjugate showed an increasing trend with an increase in copolymer dose. From in vitro test, it was found that the transduction efficiency of PPA-Ad conjugate in CAR-positive cells (A549 and H460 cells) was remarkably increased at the acidic pH condition (pH 6.2) when compared with PPA-Ad conjugate incubated under the physiological condition (pH 7.4). Interestingly, the increase in transduction efficiency was evidenced in CAR-negative cells (MDA-MB-231 and T24 cells). These results demonstrated that biocompatible and biodegradable PPA copolymers can efficiently cover the surface of Ad and can increase the transduction efficiency, and hence PPA copolymers can be a useful nanomaterial for viral vector delivery in cancer therapy.
... Excellent adhesive property is important for a hydrogel wound dressing. Adhesive hydrogels can adhere to an irregular wound site and act as a physical barrier, protecting the wound from the adverse external environment (Le et al., 2018). We tested the adhesive properties of all hydrogels using the 90°peeling test. ...
Any sort of wound injury leads to the destruction of skin integrity and wound formation, causing millions of deaths every year and accounting for 10% of death rate insight into various diseases. The ideal biological wound dressings are expected to possess extraordinary mechanical characterization, cytocompatibility, adhesive properties, antibacterial properties, and conductivity of endogenous electric current to enhance the wound healing process. Recent studies have demonstrated that biomedical hydrogels can be used as typical wound dressings to accelerate the whole healing process due to them having a similar composition structure to skin, but they are also limited by ideal biocompatibility and stable mechanical properties. To extend the number of practical candidates in the field of wound healing, we designed a new structural zwitterion poly[3-(dimethyl(4-vinylbenzyl) ammonium) propyl sulfonate] (SVBA) into a poly-acrylamide network, with remarkable mechanical properties, stable rheological property, effective antibacterial properties, strong adsorption, high penetrability, and good electroactive properties. Both in vivo and in vitro evidence indicates biocompatibility, and strong healing efficiency, indicating that poly (AAm-co-SVBA) (PAS) hydrogels as new wound healing candidates with biomedical applications.
... By replacing cationic tertiary amine groups in PAEU with pH-sensitive anionic sulfamethazine groups, amphiphilic multiblock polyurethanes can be synthesized for preparation of hydrogels that can be injected at room temperature and high pH (pH 8.5). 47 These pH-sensitive anionic multiblock polyurethanes (AMPU) have better mechanical properties and tissue adhesion than PAEU because of the presence of sulfamethazine groups. By controlling the molar ratio of monomers, AMPU hydrogels with good injectability and in vivo gel properties can be obtained. ...
... Hydrophilic groups are also responsible for the interactions of hydrogel with the biological tissues 15,16 . Hydrogels are advantageous for biomedical applications due to their easy encapsulation of the drug, equal distribution within an irregular shaped defects and also permitting to remain at specific site 17,18 . ...
pH responsive hydrogels have gained much attraction in biomedical fields. We have formulated ternary hydrogel films as a new carrier of drug. Polyelectrolyte complex of chitosan/guar gum/polyvinyl pyrrolidone cross-linked via sodium tripolyphosphate was developed by solution casting method. Fourier transform infrared spectroscopy, scanning electron microscopy and thermogravimetric analysis were conducted to examine the interactions between the polymeric chains, surface morphology and thermal stability, respectively. The swelling tests resulted that the swelling was reduced with the increase in the concentration of crosslinker due to the more entangled arrangement and less availability of pores in hydrogels. Ciprofloxacin hydrochloride was used as a model drug and its release in simulated gastric fluid, simulated intestinal fluid and phosphate buffer saline solution was studied. pH responsive behaviour of the hydrogels have subjected these hydrogels for drug release applications.
... 16 State-of-the-art mussel-inspired bioadhesives primarily involve chemical grafting of catechol groups onto different natural and synthetic backbones to introduce adhesive properties to the polymers. 17 However, the reaction yield and potential grafting sites to conjugate catechol groups in such approaches are often limited. The activation of the adhesive function in the mussel-inspired hydrogels differs from polymer backbone to backbone and requires specific processing. ...
Injectable hydrogels are of gel technology in the laboratory that improves the need for gel kinetic control. They have a carrier property in three dimensions, biocompatibility and aggressive and adjustable administration for prescription. Hydrogels have been highly regarded for drug delivery and tissue engineering by injecting mild conditions in biomedical conditions. Due to the benefits of injectable hydrogels, various factors continue to prevent clinical needs. This chapter describes recent types of injectable hydrogels manufacturing and progress.
Since 3D printing can be used to design implants according to the specific conditions of patients, it has become an emerging technology in tissue engineering and regenerative medicine. How to improve the mechanical, elastic and adhesion properties of 3D-printed photocrosslinked hydrogels is the focus of cartilage tissue repair and reconstruction research.
We established a strategy for toughening hydrogels by mixing GelMA-DOPA (GD), which is prepared by coupling dopamine (DA) with GelMA, with HAMA, bacterial cellulose (BC) to produce composite hydrogels (HB–GD). HB–GD hydrogel scaffolds were characterized in vitro by scanning electron microscopy (SEM), Young’s modulus, swelling property and rheological property tests. And biocompatibility and chondrogenic ability were tested by live/dead staining, DNA quantitative analysis and immunofluorescence staining. Combined with 3D bioprinting technology, mouse chondrocytes (ADTC5) were added to form a biological chain to construct an in vitro model, and the feasibility of the model for nasal cartilage regeneration was verified by cytology evaluation.
With the increase of GD concentration, the toughness of the composite hydrogel increased (47.0 ± 2.7 kPa (HB–5GD)–158 ± 3.2 kPa (HB–20GD)), and it had excellent swelling properties, rheological properties and printing properties. The HB–GD composite hydrogel promoted the proliferation and differentiation of ATDC5. Cells in 3D printed scaffolds had higher survival rates (> 95%) and better protein expression than the encapsulated cultures.
The HB–10GD hydrogel can be made into a porous scaffold with precise shape, good internal pore structure, high mechanical strength and good swelling rate through extrusion 3D printing.
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Hydrogels have established their significance as prominent biomaterials within the realm of biomedical research. However, injectable hydrogels have garnered greater attention compared with their conventional counterparts due to their excellent minimally invasive nature and adaptive behavior post-injection. With the rapid advancement of emerging chemistry and deepened understanding of biological processes, contemporary injectable hydrogels have been endowed with an "intelligent" capacity to respond to various endogenous/exogenous stimuli (such as temperature, pH, light and magnetic field). This innovation has spearheaded revolutionary transformations across fields such as tissue engineering repair, controlled drug delivery, disease-responsive therapies, and beyond. In this review, we comprehensively expound upon the raw materials (including natural and synthetic materials) and injectable principles of these advanced hydrogels, concurrently providing a detailed discussion of the prevalent strategies for conferring stimulus responsiveness. Finally, we elucidate the latest applications of these injectable "smart" stimuli-responsive hydrogels in the biomedical domain, offering insights into their prospects.
The healing of diabetic wounds is hindered by various factors, including bacterial infection, macrophage dysfunction, excess proinflammatory cytokines, high levels of reactive oxygen species, and sustained hypoxia. These factors collectively impede cellular behaviors and the healing process. Consequently, this review presents intelligent hydrogels equipped with multifunctional capacities, which enable them to dynamically respond to the microenvironment and accelerate wound healing in various ways, including stimuli ‐responsiveness, injectable self‐healing, shape ‐memory, and conductive and real‐time monitoring properties. The relationship between the multiple functions and wound healing is also discussed. Based on the microenvironment of diabetic wounds, antibacterial, anti‐inflammatory, immunomodulatory, antioxidant, and pro‐angiogenic strategies are combined with multifunctional hydrogels. The application of multifunctional hydrogels in the repair of diabetic wounds is systematically discussed, aiming to provide guidelines for fabricating hydrogels for diabetic wound healing and exploring the role of intelligent hydrogels in the therapeutic processes.
The treatment of chronic and non-healing wounds in diabetic patients remains a major medical problem. Recent reports have shown that hydrogel wound dressings might be an effective strategy for treating diabetic wounds due to their excellent hydrophilicity, good drug-loading ability and sustained drug release properties. As a typical example, hyaluronic acid dressing (Healoderm) has been demonstrated in clinical trials to improve wound-healing efficiency and healing rates for diabetic foot ulcers. However, the drug release and degradation behavior of clinically-used hydrogel wound dressings cannot be adjusted according to the wound microenvironment. Due to the intricacy of diabetic wounds, antibiotics and other medications are frequently combined with hydrogel dressings in clinical practice, although these medications are easily hindered by the hostile environment. In this case, scientists have created responsive-hydrogel dressings based on the microenvironment features of diabetic wounds (such as high glucose and low pH) or combined with external stimuli (such as light or magnetic field) to achieve controllable drug release, gel degradation, and microenvironment improvements in order to overcome these clinical issues. These responsive-hydrogel dressings are anticipated to play a significant role in diabetic therapeutic wound dressings. Here, we review recent advances on responsive-hydrogel dressings towards diabetic wound healing, with focus on hydrogel structure design, the principle of responsiveness, and the behavior of degradation. Last but not least, the advantages and limitations of these responsive-hydrogels in clinical applications will also be discussed. We hope that this review will contribute to furthering progress on hydrogels as an improved dressing for diabetic wound healing and practical clinical application.
Wound healing following trauma, illness, or surgery is a complex process and is comprised of a particularly fragile sequence of biochemical events that are susceptible to interruption or failure, which can lead to non-healing chronic wounds, scarring and other issues. Non-healing wounds are also commonly associated with diabetes, arterial disease, infection, and the metabolic deficiencies of aging. Treatment of dermal wounds can therefore be challenging, and as such the ability to localise the effect of drugs and treatments to promote healing through protective materials is an attractive area of research.
This book introduces the essential areas of skin anatomy and the wound healing process, and how this can be disrupted by various pathologies, and proceeds to outline how biomaterials and devices for dermal drug delivery (including controlled delivery via stimuli-responsive devices) can be utilised in effective wound management. This book is an ideal companion for postgraduates and researchers in a variety of disciplines including biomedical engineering, biomaterials, drug development and delivery, formulation science and tissue engineering.
Tissue loss through injury, surgery, and disease motivates the development of new biomaterials to enable tissue repair and regeneration. Emerging at the interface between bioadhesives and regenerative medicine, a new generation of regenerative bioadhesives is created to possess dual functions of seamless tissue adhesion and effective tissue repair. This bioadhesive innovation has wide clinical applications, ranging from wound management to the regeneration of musculoskeletal tissues such as tendons and intervertebral discs. This perspective covers the design principles of regenerative bioadhesives in considering both mechanical and biological elements. Case studies of regenerative bioadhesives for load‐bearing organs such as skin, tendon, and intervertebral discs are presented here. Finally, immediate opportunities and future perspectives are outlined to further advance the field of regenerative bioadhesives.
Type 2 Diabetes Mellitus (T2D) is a chronic, obesity-related, and inflammatory disorder characterized by insulin resistance, inadequate insulin secretion, hyperglycemia, and excessive glucagon secretion. Exendin-4 (EX), a clinically established antidiabetic medication that acts as a glucagon-like peptide-1 receptor agonist, is effective in lowering glucose levels and stimulating insulin secretion while significantly reducing hunger. However, the requirement for multiple daily injections due to EX's short half-life is a significant limitation in its clinical application, leading to high treatment costs and patient inconvenience. To address this issue, we developed an injectable hydrogel system that can provide sustained EX release at the injection site, reducing the need for daily injections. In this study, we employed the electrospray technique to form EX@CS nanospheres by electrostatic interaction between cationic chitosan (CS) and negatively charged EX. These nanospheres were uniformly dispersed in a pH-temperature responsive pentablock copolymer, which forms micelles and undergoes sol-to-gel transition at physiological conditions. Following injection, the hydrogel gradually degraded, exhibiting excellent biocompatibility. The EX@CS nanospheres were subsequently released, maintaining therapeutic levels for over 72 hours compared to free EX solution. Our findings demonstrate that the pH-temperature responsive hydrogel system containing EX@CS nanospheres could be a promising platform for the treatment of T2D. This article is protected by copyright. All rights reserved.
Introduction:
Drug treatment is one of the main ways of coping with disease today. For the disadvantages of drug management, thermosensitive hydrogel is used as a countermeasure, which can realize the simple sustained release of drugs and the controlled release of drugs in complex physiological environments.
Areas covered:
This paper talks about thermosensitive hydrogels that can be used as drug carriers. The common preparation materials, material forms, thermal response mechanism, characteristics of thermosensitive hydrogels for drug release and main disease treatment applications are reviewed.
Expert opinion:
When thermosensitive hydrogels are used as drug loading and delivery platforms, desired drug release patterns and release profiles can be tailored by selecting raw materials, thermal response mechanisms, and material morphology. The properties of hydrogels prepared from synthetic polymers will be more stable than natural polymers. Integrating multiple thermosensitive mechanisms or different kinds of thermosensitive mechanisms on the same hydrogel is expected to realize the spatiotemporal differential delivery of multiple drugs under temperature stimulation. The industrial transformation of thermosensitive hydrogels as drug delivery platforms needs to meet some important conditions.
Wound healing is a complex and dynamic process, in which the pH value plays an important role in reflecting the wound status. Wound dressings are materials that are able to accelerate the healing process. Among the multifunctional advanced wound dressings developed in recent years, pH-responsive wound dressings, especially hydrogels, show great potential owing to their unique properties of adjusting their functions according to the wound conditions, thereby allowing the wound to heal in a regulated manner. However, a comprehensive review of pH-responsive wound dressings is lacking. This review summarizes the design strategies and advanced functions of pH-responsive hydrogel wound dressings, including their excellent antibacterial properties and significant pro-healing abilities. Other advanced pH-responsive materials, such as nanofibers, composite films, nanoparticle clusters, and microneedles, are also classified and discussed. Next, the pH-monitoring functions of pH-responsive wound dressings and the related pH indicators are summarized in detail. Finally, the achievements, challenges, and future development trends of pH-responsive wound dressings are discussed.
Simultaneous sustained release of cancer vaccines and immunomodulators may effectively trigger durable immune responses and avoid multiple administrations. Here, we established a biodegradable microneedle (bMN) based on a biodegradable copolymer matrix made of polyethylene glycol (PEG) and poly(sulfamethazine ester urethane) (PSMEU). This bMN was applied to the skin and slowly degraded in the epidermis/dermis layers. Then, the complexes composed of a positively charged polymer (DA3), cancer DNA vaccine (pOVA), and toll-like receptor 3 agonist poly(I/C) were synchronously released from the matrix in a pain-free manner. The whole microneedle patch was fabricated with two layers. The basal layer was formed using polyvinyl pyrrolidone/polyvinyl alcohol that could be rapidly dissolved upon applying the microneedle patch to the skin, whereas the microneedle layer was formed by complexes encapsulating biodegradable PEG-PSMEU, which was stuck at the injection site for sustained release of therapeutic agents. According to the results, 10 days is the time for the complexes to be completely released and express specific antigens in antigen-presenting cells in vitro and in vivo. It is noteworthy that this system could successfully elicit cancer-specific humoral immune responses and inhibit metastatic tumors in the lungs after a single shot of immunization.
“Smart” biomaterials that are responsive to pathological abnormalities are an appealing class of therapeutic platform for the development of personalized medications. Development of such therapeutic platform requires novel techniques that...
Polymer nanohybrid-based smart materials are considered promising platforms for targeted drug delivery and wound healing management. These systems have advantages over conventional systems where precise drug delivery and improved wound healing are required. Synthetic and naturally derived polymers with different nanomaterials are often utilized to develop these platforms. Different approaches, including electrospinning and three-dimensional printing (3D), are frequently explored to fabricate smart platforms. These platforms may be in form of patches, 3D-printed structures, or soft nano-robots. The biological activities of these promising platforms are profoundly affected by different factors, including pH, the temperature of local environments, external stimuli such as electric and magnetic fields, and the physicochemical properties of the developed platforms. The present chapter briefly discussed different polymer nanohybrid-based smart platforms for controlled drug release and wound healing applications. The materials (polymers and nanomaterials) used to prepare the smart platforms were highlighted. The effects of different stimuli (pH, temperature, electric and magnetic fields) on the biological activities of these platforms were also discussed. We anticipate that the present chapter may provide important information about smart polymeric platforms for controlled cargo delivery and wound healing management.
The current antibacterial wound dressings with antibiotic substances or metal bactericidal agents may lead to severe multidrug resistance and poor biocompatibilities. Herein, we report an inherent antibacterial hydrogel constructed by only two naturally small molecules gallic acid (GA) and diammonium glycyrrhizinate (DG) for promoting Staphylococcus aureus (S. aureus)-infected wound healing. The resultant GAD hydrogel can be fabricated by co-assembly of these two materials through simple steps. Thanks to the incorporation of GA and DG, GAD hydrogel enabled a strong mechanical performance and great self-healing property with a sustained-release of drugs into skin wounds. Moreover, the cell viability assays showed that GAD hydrogel had good cytocompatibility by promoting cell proliferation and migration. In addition, GAD hydrogel had broad antibacterial efficiency against both Gram-positive and Gram-negative bacteria. Taken together, GAD hydrogel is a promising dressing to accelerate bacterial-infected wound healing through reconstructing an intact and thick epidermis without antibiotics or cytokines.
Hydrogels, based on natural polymers, such as hyaluronic acid, are gaining an increasing popularity because of their biological activity. The antibacterial effect of ozone is widely known and used, but the instability the gas causes, severely limits its application. Ozone entrapment in olive oil by its reaction with an unsaturated bond, allows for the formation of stable, therapeutically active ozone derivatives. In this study, we obtained an innovative hydrogel, based on hyaluronic acid containing micro/nanocapsules of ozonated olive oil. By combination of the biocompatible polymer with a high regenerative capacity and biologically active ingredients, we obtained a hydrogel with regenerative properties and a very weak inhibitory effect against both bacterial commensal skin microbiota and pathogenic Candida-like yeasts. We assessed the stability and rheological properties of the gel, determined the morphology of the composite, using scanning electron microscopy (SEM) and particle size by the dynamic light scattering (DLS) method. We also performed Attenuated total reflectance Fourier transform infrared (FTIR-ATR) spectroscopy. The functional properties, including the antimicrobial potential were assessed by the microbiological analysis and in vitro testing on the HaCat human keratinocyte cell line. The studies proved that the obtained emulsions were rheologically stable, exhibited an antimicrobial effect and did not show cytotoxicity in the HaCat keratinocyte model.
Injectable hydrogels can support the body's innate healing capability by providing a temporary matrix for host cell ingrowth and neovascularization. The clinical adoption of current injectable systems remains low due to their cumbersome preparation requirements, device malfunction, product dislodgment during administration, and uncontrolled biological responses at the treatment site. To address these challenges, a fully synthetic and ready‐to‐use injectable biomaterial is engineered that forms an adhesive hydrogel that remains at the administration site regardless of defect anatomy. The product elicits a negligible local inflammatory response and fully resorbs into nontoxic components with minimal impact on internal organs. Preclinical animal studies confirm that the engineered hydrogel upregulates the regeneration of both soft and hard tissues by providing a temporary matrix to support host cell ingrowth and neovascularization. In a pilot clinical trial, the engineered hydrogel is successfully administered to a socket site post tooth extraction and forms adhesive hydrogel that stabilizes blood clot and supports soft and hard tissue regeneration. Accordingly, this injectable hydrogel exhibits high therapeutic potential and can be adopted to address multiple unmet needs in different clinical settings.
Injectable bioadhesives offer several advantages over conventional staples and sutures in surgery to seal and close incisions or wounds. Despite the growing research in recent years few injectable bioadhesives are available for clinical use. This review summarizes the key chemical features that enable the development and improvements in the use of polymeric injectable hydrogels as bioadhesives or sealants, their design requirements, the gelation mechanism, synthesis routes, and the role of adhesion mechanisms and strategies in different biomedical applications. It is envisaged that developing a deep understanding of the underlying materials chemistry principles will enable researchers to effectively translate bioadhesive technologies into clinically‐relevant products. Bioadhesives are increasingly emerging as the preferred alternatives to surgical sutures by offering several advantages
Nanoparticle-hydrogel systems have recently emerged as a class of interesting hybrid materials with immense potential for several biomedical applications. Remarkably, the incorporation of nanoparticles into a hydrogel may yield synergistic benefits lacking in a singular system. However, most synthetic strategies require laborious steps to achieve the system, severely restricting the process of translational research. Herein, a facile strategy to access a two-in-one system comprising two distinct polyurethane (PU)-based micellar systems is demonstrated and applied as a novel sustained gene delivery platform, where the two PUs are synthesized similarly but with slightly different compositions. One PU forms cationic micelles that complex with plasmid DNA (pDNA), which are loaded into a thermogel formed by another PU micellar system for the prolonged release of pDNA micelleplexes. Specifically, a thermogelling multiblock PU copolymer (denoted as EPH) was synthesized via the step-growth polymerization of poly(ethylene glycol), poly(propylene glycol), and poly(3-hydroxybutyrate). By further introducing a cationic extender, 3-(dimethylamino)-1,2-propanediol, into the reaction feed, a series of cationic PUs (denoted as EPHD) with varying compositions were obtained. The EPHDs formed positively charged micelles in aqueous solutions, efficiently condensed pDNA into nano-sized micelleplexes (<200 nm) at optimized w/w ratios, and mediated transient green fluorescence protein expression in HEK293T cells at 48 h post-transfection. On the other hand, aqueous EPH solution (4 wt %) was injectable at 4 °C and rapidly gelled upon heating to 37 °C to form a stable hydrogel depot. EPHD/pDNA micelleplexes were easily loaded into EPH by mixing the solutions at 4 °C, before heating to 37 °C, leading to the resultant hydrogel system. The in vitro release study revealed that while free pDNA loaded in the thermogel was completely released in 2 weeks, the release of EPHD/pDNA micelleplexes was prolonged to at least 28 days, suggesting substantial micelleplex-hydrogel interactions. Intact, bioactive, and noncytotoxic EPHD/pDNA micelleplexes in the release media were proved by gel retardation, in vitro gene transfection, and CCK-8 cytotoxicity assay results, respectively. Collectively, this work presents a simple approach to achieving and optimizing a novel two-in-one nanoparticle-hydrogel system for the prolonged delivery of pDNA and may be promising for long-term gene delivery applications.
Enzyme-mediated crosslinked hydrogels as soft materials for biomedical applications have gained considerable attention. In this article, we studied the effect of post-treatment with tannic acid on adhesiveness and physiochemical properties of an enzymatically crosslinked hydrogel based on chitosan and alginate. The hydrogels were soaked in TA solution at different pH (3, 5.5, 7.4, and 9) and concentrations (1, 10, 20, 30 TA wt%). Increasing the TA concentration to 30 TA wt% and pH (up to 7.4) increased the TA loading and TA release. TA post-treatment reduced the swelling ratio and degradation rate of the hydrogels due to the formation of hydrogen bonding between TA molecules, chitosan, and alginate chains due to the increasing the secondary crosslinking density. TA-reinforced hydrogels with 30 % TA (Gel-TA 30) exhibited significantly high adhesive strength (up to 18 kPa), storage modulus (40 kPa), and antioxidant activity (>96 %), antibacterial activity, and proliferation and viability of 3 T3-L1 fibroblast cells.
The present work dealt with the development of physically cross-linked injectable hydrogels with potential applications in tissue engineering. The hydrogels were composed of a ternary mixture of a polyanion and a polyampholyte, hyaluronic acid (HA) and gelatin, respectively, bridged by cationic cellulose nanocrystals (cCNCs). A 3D network is formed by employing attractive electrostatic interactions and hydrogen bonding between these components under physiological conditions. The hydrogels demonstrated low viscosity at high stresses, enabling easy injection, structural stability at low stresses (<15 Pa), and nearly complete structure recovery within several minutes. Increasing the cCNC content (>3%) reduced hydrogel swelling and decelerated the degradation in phosphate-buffered saline as compared to that in pure HA and HA–gelatin samples. Biological evaluation of the hydrogel elutions showed excellent cell viability. The proliferation of fibroblasts exposed to elutions of hydrogels with 5% cCNCs reached ∼200% compared to that in the positive control after 11 days. Considering these results, the prepared hydrogels hold great potential in biomedical applications, such as injectable dermal fillers, 3D bioprintable inks, or 3D scaffolds to support and promote soft tissue regeneration.
Wound management remains a significant problem in the biomedical fields despite the availability of advanced materials. There is also a pressing need to develop materials that can support tissue regeneration. The factors that hamper the progress in wound-dressing development and tissue regenerative medicine include microbial infections, underlying chronic conditions in the patients, such as diabetes and cancer, neglected treatment of wounds, and malnutrition. Biomaterials have been employed for tissue regenerative medicine and wound dressing. However, some of them can delay the wound-healing process and skin regeneration as a result of their inability to provide suitable moisture and warmth for the accelerated wound-healing process, poor biodegradation and biocompatibility, poor antimicrobial properties, and toxicity. In orthopedics, bone and joint degeneration and inflammation are life-threatening conditions that afflict millions of people around the world. The properties of biomaterials must be considered to determine their suitability for orthopedics purposes. The general concerns about leaching, corrosion, mutagenicity, and absorption must be strictly addressed in biomaterials that are to be used in orthopedic applications. The features of an ideal biomaterial for orthopedic applications include rapid healing, prevention of microbial infections, affordability, aesthetic features, and biocompatibility. Injectable biomaterials have demonstrated several interesting properties in biomedical applications. This chapter discusses the properties and outcomes of injectable biomaterials, specifically injectable hydrogels, in wound care, orthopedics, and tissue-engineering applications.
The stimuli-responsiveness of injectable hydrogel has been drastically developed for the controlled release of drugs and achieved encouraging curative effects in a variety of diseases including wounds, cardiovascular diseases and tumors. The gelation, swelling and degradation of such hydrogels respond to endogenous biochemical factors (such as pH, reactive oxygen species, glutathione, enzymes, glucose) and/or to exogenous physical stimulations (like light, magnetism, electricity and ultrasound), thereby accurately releasing loaded drugs in response to specifically pathological status and as desired for treatment plan and thus improving therapeutic efficacy effectively. In this paper, we give a detailed introduction of recent progresses in responsive injectable hydrogels and focus on the design strategy of various stimuli-sensitivities and their resultant alteration of gel dissociation and drug liberation behaviour. Their application in disease treatment is also discussed. This article is protected by copyright. All rights reserved.
Several cues, including wettability, surface morphology, and porosity, affect the cellular behaviors on nanofibrous scaffolds. However, a challenging task is determining the more influential parameter on cellular behaviors. Herein, we prepared two sets of polycaprolactone (PCL)-based electrospun nanofibrous scaffolds, viz. surface morphology-altered PCL (SMA PCL) scaffolds and hydrophilic PCL-chitosan scaffolds with different chitosan content. We further investigated the scaffolds' cell attachment and proliferation ability to determine which is a predominant factor, wettability, or surface morphology? Water contact angle and alternative current impedance analyses revealed that incorporating chitosan to PCL increased the wettability and dielectric properties. In contrast, alterations in surface morphology did not show any significant changes to the properties mentioned above of neat PCL. Different solvent compositions (CHCl3/DMSO) caused cylindrical and smooth PCL nanofiber to adopt porous, wristed, or flat fibrous structures. The fibroblasts cell studies revealed that both PCL-chitosan and SMA PCL scaffolds had similar cell proliferation profiles on day 1. However, the former scaffolds showed a statistically significant difference from the latter ones on days 3 and 5. In conclusion, we suggest that increasing the wettability of nanofibrous scaffolds is more influential in directing cellular behaviors than surface morphology modification.
The clinical acceleration of skin autogenous healing remains a great challenge, especially in the early stage after injury. In this work, a novel directly injectable hydrogel with high self-adaptability is designed as a provisional matrix to close the apposition of wound edges, using carboxymethyl cellulose and poly (γ-glutamic acid) through Schiff-base reaction. Benefiting from the dynamic covalent cross-linking structure, the functional biodegradable hydrogels are easy to prepare (gel time 5–180 s), demonstrating adequate mechanical strength (40–120 kPa), anti-fatigue abilities, and rapid self-healing (5–10 min at skin defect). Furthermore, the hydrogels exhibit biocompatibility and proliferation-promoting activity with murine fibroblasts. In the full-thickness dermal animal models, it significantly promoted collagen deposition, skin-function restoration, and VEGF expression. This hydrogel shows potential as a dressing available for skin regeneration during the healing of dermal injuries.
Blindness is one of the most feared disabilities. From cataracts and glaucoma to age‐related macular degeneration and retinal vascular diseases, ocular diseases have adverse impacts on patients and pose a huge burden to the healthcare system. The World Health Organization estimates that out of 2.2 billion people with visual impairment, almost half of the cases can be prevented or has yet to be addressed. This presents an urgent clinical and societal need to be met. Temperature‐sensitive hydrogels are one of the most biocompatible materials, which can be applied into the eye. By exploiting physiological temperature as a stimulus for in situ gel formation, control of the mechanical properties, rate of drug release, and biomechanical interactions can be tuned. They are very versatile and have immense potential in ocular applications by acting as vitreous substitutes in retinal surgery or topical eye drops and lenses for ocular discomfort and inflammation. In this article, we provide a review of the recent developments in temperature‐responsive polymers in ophthalmic therapy in the past 5 years including retinal detachment, retinal vascular diseases, dry eyes, cataracts, age‐related macular degeneration, and glaucoma.
Due to the promising properties of chitosan for biomedical engineering applications like biodegradability, biocompatibility, and non-toxicity, it is one of the most interesting biopolymers in this field. Therefore, Chitosan and its derivatives have attracted great attention in vast variety of biomedical applications. In the current paper, different types of chitosan-based bioadhesives including passive and active and their different types of external stimuli response structure such as thermo, pH and Light responsive systems are discussed. Different bioadhesives mechanisms with chitosan as an adhesive agent or main polymer component and some examples were also presented. Chitosan based bioadhesives and their potential biomedical applications in drug delivery systems, suture less surgery, wound dressing and hemostatic are also discussed. The results confirmed wound healing, hemostatic and bioadhesion capabilities of the chitosan bioadhesives and its great potential for biomedical applications.
How to improve the therapeutic efficacy of cell delivery during mechanical injection has been a great challenge for tissue engineering. Here, we present a facile strategy based on dynamic chemistry to prepare injectable hydrogels for efficient stem cell delivery using hyaluronic acid (HA) and poly(γ-glutamic acid) (γ-PGA). The combination of the guest–host (GH) complexation and dynamic hydrazone bonds enable the HA/γ-PGA hydrogels with physical and chemical dual dynamic network and endow hydrogels a stable structure, rapid self-healing ability, and injectability. The mechanical properties, self-healing ability, and adaptability can be programmed by changing the ratio of GH network to hydrazine bond cross-linked network. Benefitting from the dynamic cross-linking networks, mild preparation process, and cytocompatibility of HA/γ-PGA hydrogels, bone marrow mesenchymal stem cells (BMSCs) show high cell viability in this system following mechanical injection. Moreover, HA/γ-PGA hydrogels can promote BMSC proliferation and upregulate the expression of cartilage-critical genes. Notably, in a rabbit auricular cartilage defect model, BMSC-laden HA/γ-PGA hydrogels can effectively promote cartilage regeneration. Together, we propose a general strategy to develop injectable self-healing HA/γ-PGA hydrogels for effective stem cell delivery in cartilage tissue engineering.
Gelatin-based bioadhesives are suitable for the treatment of wounds due to their inherent biocompatibility, lack of immunogenicity, and potential for modification. However, common limitations with such adhesives include their adhesive strength and versatility. In the present study, a multifunctional injectable temperature-sensitive gelatin-based adhesive double-network hydrogel (DNGel) was engineered using facile dual-syringe methodology. An integrative crosslinking strategy utilized the complexation of catechol-Fe³⁺ and NIPAAm-methacryloyl. As anticipated, the DNGel exhibited multifunctional therapeutic properties, namely temperature-sensitivity, mechanical flexibility, good adhesive strength, injectability, self-healing capability, antibacterial activity, and the capability to enable hemostasis and wound healing. The bioinspired dynamic double-network was stabilized by a number of molecular interactions between components in the DNGel, providing multifunctional therapeutic performance. In addition, comprehensive in vitro and in vivo testing confirmed that the adhesive hydrogel exhibited effective antihemorrhagic properties and accelerated wound healing by the promotion of revascularization, representing considerable potential as a next-generation multifunctional smart adhesive patch.
Introduction: The development of wound dressing materials that combine healing properties, ability to self-repair the material damages, skin-friendly adhesive nature, and competent mechanical properties have surpassing functional importance in healthcare. Due to their specificity, hydrogels have been recognized as a new gateway in biological materials to treat dysfunctional tissues. The design and creation of injectable hydrogel-based scaffolds have extensively progressed in recent years to improve their therapeutic efficacy and to pave the way for their easy minimally invasive administration. Hence, injectable hydrogel biomaterials have been prepared to eventually translate into minimally invasive therapy and pose a lasting effect on regenerative medicine.
Areas Covered: This review highlights the recent development of adhesive and injectable hydrogels that have applications in wound healing and wound dressing. Such hydrogel materials are not only expected to improve therapeutic outcomes but also to facilitate the easy surgical process in both wound healing and dressing.
Expert Opinion: Wound healing seems to be an appealing approach for treating countless life-threatening disorders. With the average increase of life expectancy in human societies, an increase in demand for injectable skin replacements and drug delivery carriers for chronic wound healing is expected.
Regenerative medicine is a field of science that has shown enormous applications for efficient therapy and has been advanced by recent sophisticated achievements in bioengineering. Modern techniques deployed in manufacturing tissues and designing structures, which are functional in preserving, restoring, and regenerating damaged tissues and organs, have enhanced medicine and health care. Methods of merging biomimetic materials, cells, and bioactive molecules are critical in advancing the revival of wounded tissues or therapeutic systems. In recent decades, one of the most popular materials used for engineering tissues is the hydrogel-based scaffolds. They represent the ability to configure a distinct 3D structure that provides the cells within the tissues with elegant mechanical support for the cells in the engineered tissues and replicate the native extracellular matrix. In this chapter, as an important class of stem cell vehicles, hydrogels are articulated, and their fabrications and applications for tissue regeneration are discussed. We focus on the application of the hydrogels for 3D cultures in regenerating different tissues, such as skin, bone cartilage, vascular, cardiac, and neural tissue regeneration.
For the past decades, several bioadhesives have been developed to replace conventional wound closure medical tools such as sutures, staples, and clips. The bioadhesives are easy to use and can minimize tissue damage. They are designed to provide strong adhesion with stable mechanical support on tissue surfaces However, this monofunctionality of the bioadhesives hinders their practical applications. In particular, a bioadhesive can lose its intended function under harsh tissue environments or delay tissue regeneration during wound healing. Based on several natural and synthetic biomaterials, functional bioadhesives have been developed to overcome the aforementioned limitations. The functional bioadhesives are designed to have specific characteristics such as antimicrobial, cell infiltrative, stimuli-responsive, electrically conductive, and self-healing to ensure stability under harsh tissue conditions, facilitate tissue regeneration, and effectively monitor biosignals. Herein, we thoroughly review the functional bioadhesives from their fundamental background to recent progress with their practical applications for the enhancement of tissue healing and effective biosignal sensing. Furthermore, the future perspectives on the applications of functional bioadhesives and current challenges in their commercialization are also discussed.
This article is protected by copyright. All rights reserved
Hydrogels represent one of the cornerstones in tissue engineering and regenerative medicine, due to their biocompatibility and physiologically relevant properties. These inherent characteristics mean that they can be widely exploited as bioinks in 3D bioprinting for tissue engineering applications as well as injectable gels for cell therapy and drug delivery purposes. The research in these fields is booming and this book provides the reader with a terrific introduction to the burgeoning field of injectable hydrogel design, bioprinting and tissue engineering.
Edited by three leaders in the field, users of this book will learn about different classes of hydrogels, properties and synthesis strategies to produce bioinks. A section devoted to the key processing and design challenges at the hydrogel/3D bioprinting/tissue interface is also covered. The final section of the book closes with pertinent clinical applications.
Tightly edited, the reader will find this book to be a coherent resource to learn from. It will appeal to those working across biomaterials science, chemical and biomedical engineering, tissue engineering and regenerative medicine.
Adjusting biomaterial degradation profile to match tissue regeneration is a challenging issue. Herein, the biodegradable hyperbranched poly(β-amino ester)s (HP-PBAE)s were designed and synthesized via “A2 + B4” Michael addition polymerization, which displayed fast gelation with thiolated hyaluronic acid (HA-SH) via “click” thiol-ene reaction. HP-PBAE/HA-SH hydrogels showed tunable degradation profiles both in vitro and in vivo by using diamines with different alkyl chain lengths and poly(ethylene glycol) diacrylates with varied PEG spacers. The hydrogels with optimized degradation profiles encapsulating ADSCs were used as injectable hydrogels to treat two different types of humanized excisional wounds - acute wounds with faster healing rate and diabetic wounds with slower healing and neo-tissue formation. The fast-degrading hydrogel had the accelerated wound closure in acute wounds, while the slow-degrading hydrogel showed better wound healing for diabetic wounds. The results demonstrate that the new HP-PBAE-based hydrogel in combination with ADSCs can be used as a well-controlled biodegradable skin substitute, which demonstrates a promising approach in the treatment of various types of skin wounds.
Stem cells have shown substantial promise for various diseases in preclinical and clinical trials. However, low cell engraftment rates significantly limit the clinical translation of stem cell therapeutics. Numerous injectable hydrogels have been developed to enhance cell retention. Yet, the design of an ideal material with tunable properties that can mimic different tissue niches and regulate stem cell behaviors remains an unfulfilled promise. Here, an injectable poly(ethylene glycol) (PEG)-gelatin hydrogel is designed with highly tunable properties, from a multifunctional PEG-based hyperbranched polymer and a commercially available thiolated gelatin. Spontaneous gelation occurs within about 2 min under the physiological condition. Murine adipose-derived stem cells (ASCs) can be easily encapsulated into the hydrogel, which supports ASC growth and maintains their stemness. The hydrogel mechanical properties, biodegradability, and cellular responses can be finely controlled by changing hydrogel formulation and cell seeding densities. An animal study shows that the in situ formed hydrogel significantly improves cell retention, enhances angiogenesis, and accelerates wound closure using a murine wound healing model. These data suggest that injectable PEG-gelatin hydrogel can be used for regulating stem cell behaviors in 3D culture, delivering cells for wound healing and other tissue regeneration applications.
Excessive production of inflammatory chemokines can cause chronic inflammation and thus impair cutaneous wound healing. Capturing chemokine signals using wound dressing materials may offer powerful new treatment modalities for chronic wounds. Here, a modular hydrogel based on end-functionalized star-shaped polyethylene glycol (starPEG) and derivatives of the glycosaminoglycan (GAG) heparin was customized for maximal chemokine sequestration. The material is shown to effectively scavenge the inflammatory chemokines MCP-1 (monocyte chemoattractant protein–1), IL-8 (interleukin-8), and MIP-1α (macrophage inflammatory protein–1α) and MIP-1β (macrophage inflammatory protein-1β) in wound fluids from patients suffering from chronic venous leg ulcers and to reduce the migratory activity of human monocytes and polymorphonuclear neutrophils. In an in vivo model of delayed wound healing (db/db mice), starPEG-GAG hydrogels outperformed the standard-of-care product Promogran with respect to reduction of inflammation, as well as increased granulation tissue formation, vascularization, and wound closure.
A major challenge in tissue engineering is to generate a functional microvasculature that ensures proper blood perfusion and connection with surrounding tissues. Strategies such as the incorporation of growth factors have been proposed to induce the growth of new blood vessels into engineered tissue, but limitations remain. Herein a novel chitosan–fibrin (CF)-based self-healing hydrogel with a modulus of ~1.2 kPa was developed. The self-healing hydrogel was found to be injectable and to degrade ~70% in 2 weeks. Vascular endothelial cells seeded in the CF hydrogel were able to form capillary-like structures. Moreover, the injection of the CF hydrogel alone promoted angiogenesis in the perivitelline space of zebrafish and rescued the blood circulation in ischemic hindlimbs of mice. The excellent self-healing and angiogenic capacities of the hydrogel may be associated with the formation of an interpenetrating polymer network structure between chitosan and fibrin. This unique self-healing hydrogel offers new possibilities for future applications to vascular repair.
Inadequate drug loading of hydrophobic drugs is a classic problem when hydrogels are utilized as sustained-release carriers of drugs. Herein, a strategy to load plenty of hydrophobic drugs is presented. The antitumor drug 10-hydroxycamptothecin in the thermogel of poly(d,l-lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(d,l-lactic acid-co-glycolic acid) is employed. The drug is soluble in an alkaline medium, yet insoluble in a neutral/acidic medium. The crystallization is triggered after adding an alkaline drug solution into an acidic copolymer solution. The concentrated copolymer aqueous solution undergoes a sol–gel transition upon heating, faster than the crystallization. As a result, plenty of evenly dispersed drug microcrystals are formed. The in vitro and in vivo experiments indicate both high drug loading and sustained release with enhanced antitumor efficacy and reduced adverse effects. The system resolves the challenge in formulation of hydrophobic drugs in hydrogels, and is stimulating for encapsulating drugs with a soluble-insoluble transition into a material environment.
A photocleavable hydrogel system for on-demand delivery of genetic material is reported. The release of short interfering RNAs can be triggered by the application of UV light without any loss in bioactivity. This approach provides a promising external stimulus-based nucleic acid delivery platform for applications in disease therapeutics and tissue regeneration.
The use of artificial tissues in regenerative medicine is limited due to hypoxia. As a strategy to overcome this drawback, we have shown that photosynthetic biomaterials can produce and provide oxygen independently of blood perfusion by generating chimeric animal-plant tissues during dermal regeneration. In this work, we demonstrate the safety and efficacy of photosynthetic biomaterials in vivo after engraftment in a fully immunocompetent mouse skin defect model. Further, we show that it is also possible to genetically engineer such photosynthetic scaffolds to deliver other key molecules in addition to oxygen. As a proof-of-concept, biomaterials were loaded with gene modified microalgae expressing the angiogenic recombinant protein VEGF. Survival of the algae, growth factor delivery and regenerative potential were evaluated in vitro and in vivo. This work proposes the use of photosynthetic gene therapy in regenerative medicine and provides scientific evidence for the use of engineered microalgae as an alternative to deliver recombinant molecules for gene therapy.
Synthetic oligonucleotides are used to regulate gene expression through different mechanisms. Chemical modifications of the backbone of the nucleic acid and/or of the 2' moiety of the ribose can increase nuclease stability and/or binding affinity of oligonucleotides to target molecules. Here we report that transfection of 2'-F-modified phosphorothioate oligonucleotides into cells can reduce the levels of P54nrb and PSF proteins through proteasome-mediated degradation. Such deleterious effects of 2'-F-modified oligonucleotides were observed in different cell types from different species, and were independent of oligonucleotide sequence, positions of the 2'-F-modified nucleotides in the oligonucleotides, method of delivery or mechanism of action of the oligonucleotides. Four 2'-F-modified nucleotides were sufficient to cause the protein reduction. P54nrb and PSF belong to Drosophila behavior/human splicing (DBHS) family. The third member of the family, PSPC1, was also reduced by the 2'-F-modified oligonucleotides. Preferential association of 2'-F-modified oligonucleotides with P54nrb was observed, which is partially responsible for the protein reduction. Consistent with the role of DBHS proteins in double-strand DNA break (DSB) repair, elevated DSBs were observed in cells treated with 2'-F-modified oligonucleotides, which contributed to severe impairment in cell proliferation. These results suggest that oligonucleotides with 2'-F modifications can cause non-specific loss of cellular protein(s).
© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in preclinically active uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.
Copyright © 2015. Published by Elsevier B.V.
Non-viral vectors are simple in theory but complex in practice. Apart from intra cellular and extracellular barriers, number of other
challenges also needs to be overcome in order to increase the effectiveness of non-viral gene transfer. These barriers are categorized
as production, formulation and storage. No one-size-fits-all solution to gene delivery, which is why in spite of various developments in
liposome, polymer formulation and optimization, new compounds are constantly being proposed and investigated. In this review, we will
see in detail about various types of non-viral vectors highlighting promising development and recent advances that had improved the
non-viral gene transfer efficiency of translating from “Bench to bedside”.
The beginning of the 21st century saw numerous protein and peptide therapeuticals both on the market and entering the final stages of clinical studies. They represent a new category of biologically originated drugs termed biologics or biologicals. Their main advantages over conventional drugs can be summarized by their high selectivity and potent therapeutic efficacy coupled with limited side effects. In addition, they exhibit more predictable behavior under in vivo conditions. However, up to now most of the formulations of biologics are designed and destined for the parenteral route of administration. As a consequence, many suffer from short plasma half-lives, resulting in their frequent administration and ultimately poor patient compliance. This review represents an attempt to address some of the challenges and promises in the product development of biologics both for parenteral and noninvasive administration. Some of the products currently in the pipeline of pharmaceutical development and corresponding perspectives are discussed in more detail.
A series of small-size polyethylenimine (PEI)-conjugated pluronic polycarbamates (PCMs) have been investigated for the ability to modulate the delivery of 2'-O-methyl phosphorothioate RNA (2'-OMePS) in vitro and in dystrophic mdx mice. The PCMs retain strong binding capacity to negatively charged oligomer as demonstrated by agarose gel retardation assay, with the formation of condensed polymer/oligomer complexes at a wide-range weight ratio from 1:1 to 20:1. The condensed polymer/oligomer complexes form 100-300 nm nanoparticles. Exon-skipping effect of 2'-OMePS was dramatically enhanced with the use of the most effective PCMs in comparison with 2'-OMePS alone in both cell culture and in vivo, respectively. More importantly, the effective PCMs, especially those composed of moderate size (2k-5kDa) and intermediate hydrophilic-lipophilic balance (7-23) of pluronics, enhanced exon-skipping of 2'-OMePS with low toxicity as compared with Lipofectamine-2000 in vitro or PEI 25k in vivo. The variability of individual PCM for delivery of antisense oligomer and plasmid DNA indicate the complexity of interaction between polymer and their cargos. Our data demonstrate the potential of PCMs to mediate delivery of modified antisense oligonucleotides to the muscle for treating muscular dystrophy or other appropriate myodegenerative diseases.Gene Therapy advance online publication, 17 October 2013; doi:10.1038/gt.2013.57.
The principles of engineering and physics have been applied to oncology for nearly 50 years. Engineers and physical scientists have made contributions to all aspects of cancer biology, from quantitative understanding of tumour growth and progression to improved detection and treatment of cancer. Many early efforts focused on experimental and computational modelling of drug distribution, cell cycle kinetics and tumour growth dynamics. In the past decade, we have witnessed exponential growth at the interface of engineering, physics and oncology that has been fuelled by advances in fields including materials science, microfabrication, nanomedicine, microfluidics, imaging, and catalysed by new programmes at the National Institutes of Health (NIH), including the National Institute of Biomedical Imaging and Bioengineering (NIBIB), Physical Sciences in Oncology, and the National Cancer Institute (NCI) Alliance for Nanotechnology. Here, we review the advances made at the interface of engineering and physical sciences and oncology in four important areas: the physical microenvironment of the tumour and technological advances in drug delivery; cellular and molecular imaging; and microfluidics and microfabrication. We discussthe research advances, opportunities and challenges for integrating engineering and physical sciences with oncology to develop new methods to study, detect and treat cancer, and we also describe the future outlook for these emerging areas.
Restoration of tissue integrity and tissue function of wounded skin are both essential for wound repair and regeneration, while synergistic promotion of the two remains elusive. Since elevated reactive oxygen species (ROS) production in the injured site has been implicated in triggering a set of deleterious effects such as cellular senescence, fibrotic scarring, and inflammation, it is speculated that alleviating oxidative stress in the microenvironment of injured site would be beneficial to promote regenerative wound healing. In this study, a highly versatile ROS-scavenging tissue adhesive nanocomposite is synthesized by immobilizing ultrasmall ceria nanocrystals onto the surface of uniform mesoporous silica nanoparticles (MSN). The ceria nanocrystals decorated MSN (MSN-Ceria) not only has strong tissue adhesion strength, but also significantly restricts ROS exacerbation mediated deleterious effects, which efficiently accelerates the wound healing process, and more importantly, the wound area exhibits an unexpected regenerative healing characteristic featured by marked skin appendage morphogenesis and limited scar formation. This strategy can also be adapted to other wound repair where both ROS-scavenging activity and tissue adhesive ability matter.
Surgical sealants have been used for sealing or reconnecting ruptured tissues but often have low adhesion, inappropriate mechanical strength, cytotoxicity concerns, and poor performance in biological environments. To address these challenges, we engineered a biocompatible and highly elastic hydrogel sealant with tunable adhesion properties by photocrosslinking the recombinant human protein tropoelastin. The subcutaneous implantation of the methacryloyl-substituted tropoelastin (MeTro) sealant in rodents demonstrated low toxicity and controlled degradation. All animals survived surgical procedures with adequate blood circulation by using MeTro in an incisional model of artery sealing in rats, and animals showed normal breathing and lung function in a model of surgically induced rat lung leakage. In vivo experiments in a porcine model demonstrated complete sealing of severely leaking lung tissue in the absence of sutures or staples, with no clinical or sonographic signs of pneumothorax during 14 days of follow-up. The engineered MeTro sealant has high potential for clinical applications because of superior adhesion and mechanical properties compared to commercially available sealants, as well as opportunity for further optimization of the degradation rate to fit desired surgical applications on different tissues.
In this work, we have synthesized a thermoresponsive copolymer, alginate-g-poly(N-isopropylacrylamide) (alginate-g-PNIPAAm), by conjugating PNIPAAm to alginate, where PNIPAAm with different molecular weight and narrow molecular weight distribution was synthesized by atomic transfer radical polymerization (ATRP). The copolymer dissolved in water or PBS buffer solution at room temperature, and formed self-assembled micelles with low critical micellization concentrations when temperature increased to above their critical micellization temperatures. At higher concentration, i.e., 7.4 wt% in water, the copolymer formed solutions at 25 C, and turned into thermosensitive hydrogels when temperature increased to the body temperature (37 C). Herein, we hypothesized that the thermoresponsive hydrogels could produce self-assembled micelles with the dissolution of the alginate-g-PNIPAAm hydrogels in a biological fluid or drug release medium. If the drug was hydrophobic, the hydrogel eventually could release and produce drug-encapsulated micelles. In our experiments, we loaded the anti-cancer drug doxorubicin (DOX) into the alginate-g-PNIPAAm hydrogels, and demonstrated that the hydrogels released DOX-encapsulated micelles in a sustained manner. The slowly released DOX-loaded micelles enhanced the cellular uptake of DOX in multidrug resistance AT3B-1 cells, showing effect overcoming the drug resistance and achieving better efficiency for killing the cancer cells. Therefore, the injectable thermoresponsive hydrogels formed by alginate-g-PNIPAAm and loaded with DOX turned into a smart drug delivery system, releasing DOX-encapsulated micelles in a sustained manner, showing great potential for overcoming the drug resistance in cancer therapy.
Stimuli-responsive hydrogels, known as smart hydrogels, are three-dimensional amphiphilic or hydrophilic polymer networks that are able to change their volume or phase, and other properties, including viscosity, structure, and dimension, in response to change in pH, temperature, and magnetic or electric field. Highly swellable, dual-responsive bovine serum albumin (BSA)-based injectable hydrogels are here prepared by the chemical conjugation of pH- and temperature-responsive oligo(sulfamethazine acrylate-co-N-isopropyacrylamide) (oligo(SMA-co-NIPAM)) copolymers on the surface of BSA through carbodiimide-mediated chemistry. The pH- and temperature-responsive oligomer-bearing BSA conjugates show rapid sol-to-gel phase transition properties. Specifically, the free flowing conjugates at high pH (pH 8.4, 23 °C) are transformed to a viscoelastic gel at the physiological condition (pH 7.4, 37 °C). The swelling ratio, gel strength, and pore size of the BSA hydrogel was tuned by altering the conjugation ratio of various lengths and compositions of oligo(SMA-co-NIPAM) copolymers to BSA. Subcutaneously administered BSA conjugate sols into the dorsal region of Sprague-Dawley rats formed an in situ gel. When the oligo(NIPAM) content in the hydrogel was high, the degradation rate of BSA hydrogels was remarkably slow, and two weeks after in vivo administration, the hydrogels with high oligo(NIPAM) had swollen more than 4-fold. An in vivo biodegradation study demonstrated that no necrosis or hemorrhage was observed in the tissues with the hydrogels. The concurrent stimuli-responsivity at the physiological condition and high elasticity suggests that these smart hydrogels may open a new avenue for hydrogel applications.
Biocompatible adhesive nanoaggregates were synthesized based on polyaspartamide copolymers grafted with octadecylamine (C18) and 3,4-dihydroxyphenylalanine (DOPA), and their adhesive properties were investigated with regard to wound healing. The chemical structure and morphology of the synthesized polyaspartamide-g-C18/DOPA nanoaggregates were analyzed using ¹H-nuclear magnetic resonance spectroscopy (¹H NMR), dynamic light scattering (DLS), and transmission electron microscope (TEM). The in vitro adhesive energy was up to 31.04 J m–2 for poly(dimethylacrylamide) gel substrates and 0.1209 MPa for mouse skin, and the in vivo wound breaking strength after 48 h was 1.8291 MPa for C57BL/6 mouse. The MTT assay demonstrated that the synthesized polymeric nanoaggregates were nontoxic. The polyaspartamide-g-C18/DOPA nanoaggregates were in vivo tested to mouse model and demonstrated successful skin adhesion, as the mouse skin was perfectly cured in their dermis within 6 d. As this material has biocompatibility and enough adhesive strength for wound closure, it is expected to be applied as a new type of bioadhesive agent in the human body.
In this study, silk fibroin and hyaluronic acid (HA) were enzymatically crosslinked to form biocompatible composite hydrogels with tunable mechanical properties similar to that of native tissues. The formation of di-tyrosine crosslinks between silk fibroin proteins via horseradish peroxidase has resulted in a highly elastic hydrogel but exhibits time-dependent stiffening related to silk self-assembly and crystallization. Utilizing the same method of crosslinking, tyramine-substituted HA forms hydrophilic and bioactive hydrogels that tend to have limited mechanics and degrade rapidly. To address the limitations of these singular component scaffolds, HA was covalently crosslinked with silk, forming a composite hydrogel that exhibited both mechanical integrity and hydrophilicity. The composite hydrogels were assessed using unconfined compression and infrared spectroscopy to reveal of the physical properties over time in relation to polymer concentration. In addition, the hydrogels were characterized by enzymatic degradation and for cytotoxicity. Results showed that increasing HA concentration, decreased gelation time, increased degradation rate, and reduced changes that were observed over time in mechanics, water retention, and crystallization. These hydrogel composites provide a biologically relevant system with controllable temporal stiffening and elasticity, thus offering enhanced tunable scaffolds for short or long term applications in tissue engineering.
Stimuli-responsive polypeptides are a promising class of biomaterials due to their tunable physicochemical and biological properties. Herein, a series of novel pH- and thermo-responsive block copolymers based on polypeptides were synthesized by ring-opening polymerization of γ-benzyl-l-glutamate-N-carboxyanhydride in the presence of poly(ethylene glycol)-diamine macroinitiator followed by aminolysis. The resulting polypeptide-based triblock copolymer, poly[(2-(dibutylamino)ethyl-l-glutamate)-co-(γ-benzyl-l-glutamate)]-poly(ethylene glycol)-b-poly[(2-(dibutylamino)ethyl-l-glutamate)-co-(γ-benzyl-l-glutamate)] (PNLG-co-PBLG-b-PEG-b-PBLG-co-PNLG), exists as a low viscous sol at low pH and temperature (≤pH 6.4, 25 °C) but it transforms to a soft gel under physiological conditions (pH 7.4 and 37 °C). The physical properties of the polypeptide gel can be tuned by controlling the ratio between hydrophobic PBLG and pH-sensitive PNLG blocks. The polypeptide-based copolymer did not show any noticeable cytotoxicity to fibroblast cells in vitro. It was found that subcutaneous injection of the polypeptide copolymer solution into the dorsal region of Sprague-Dawley (SD) rats formed a gel instantly without major inflammation. The gels were completely biodegraded in six weeks and found to be bioresorbable. Human growth hormone (hGH)-loaded polypeptide-based biodegradable copolymer sols readily formed a viscoelastic gel that inhibited an initial burst and prolonged the hGH release for one week. Overall, due to their bioresorbable and sustained release protein characteristics, polypeptide hydrogels may serve as viable platforms for therapeutic protein delivery and the surface tunable properties of polypeptide hydrogels can be exploited for other potential therapeutic proteins.
Adhesive hydrogels are attractive biomaterials for various applications, such as electronic skin, wound dressing, and wearable devices. However, fabricating a hydrogel with both adequate adhesiveness and excellent mechanical properties remains a challenge. Inspired by the adhesion mechanism of mussels, we used a two-step process to develop an adhesive and tough polydopamine-clay-polyacrylamide (PDA-clay-PAM) hydrogel. Dopamine was intercalated into clay nanosheets and limitedly oxidized between the layers, resulting in PDA-intercalated clay nanosheets containing free catechol groups. Acrylamide monomers were then added and in situ polymerized to form the hydrogel. Unlike previous single-use adhesive hydrogels, our hydrogel showed repeatable and durable adhesiveness. It adhered directly on human skin without causing an inflammatory response and was easily removed without causing damage. The adhesiveness of this hydrogel was attributed to the presence of enough free catechol groups in the hydrogel, which were created by controlling the oxidation process of the PDA in the confined nanolayers of clay. This mimicked the adhesion mechanism of the mussels, which maintain a high concentration of catechol groups in the confined nanospace of their byssal plaque. The hydrogel also displayed superior toughness, which resulted from nano-reinforcement by clay and PDA-induced cooperative interactions with the hydrogel networks. Moreover, the hydrogel favored cell attachment and proliferation owning to the high cell affinity of PDA. Rat full-thickness skin defect experiments demonstrated that the hydrogel was an excellent dressing. This free-standing, adhesive, tough, and biocompatible hydrogel may be more convenient for surgical applications than adhesives that involve in situ gelation and extra agents.
Injectable self-healing hydrogel dressing with multifunctional properties including anti-infection, anti-oxidative and conductivity promoting wound healing process will be highly desired in wound healing application and its design is still a challenge. We developed a series of injectable conductive self-healed hydrogels based on quaternized chitosan-g-polyaniline (QCSP) and benzaldehyde group functionalized poly(ethylene glycol)-co-poly(glycerol sebacate) (PEGS-FA) as antibacterial, anti-oxidant and electroactive dressing for cutaneous wound healing. These hydrogels presented good self-healing, electroactivity, free radical scavenging capacity, antibacterial activity, adhesiveness, conductivity, swelling ratio, and biocompatibility. Interestingly, the hydrogel with an optimal crosslinker concentration of 1.5 wt% PEGS-FA showed excellent in vivo blood clotting capacity, and it significantly enhanced in vivo wound healing process in a full-thickness skin defect model than quaternized chitosan/PEGS-FA hydrogel and commercial dressing (Tegaderm™ film) by upregulating the gene expression of growth factors including VEGF, EGF and TGF-β and then promoting granulation tissue thickness and collagen deposition. Taken together, the antibacterial electroactive injectable hydrogel dressing prolonged the lifespan of dressing relying on self-healing ability and significantly promoted the in vivo wound healing process attributed to its multifunctional properties, meaning that they are excellent candidates for full-thick skin wound healing.
The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.
Diabetes, a global epidemic, has become a serious threat to public health. The present study is aimed at constructing an injectable thermosensitive PEG/polyester hydrogel formulation of liraglutide (Lira), a "smart" anti-diabetic polypeptide, in long-acting treatment of type 2 diabetes mellitus. Three thermosensitive poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) (PCGA-PEG-PCGA) triblock copolymers with similar molecular weights but different ε-caprolactone/glycolide (CL/GA) ratios were synthesized. The polymer aqueous solutions exhibited free-flowing sols at room temperature and formed in situ hydrogels at body temperature. While the different bulk morphologies, stabilities of aqueous solutions, and the varying in vivo persistence time of hydrogels in ICR mice were found among the three copolymers, all the Lira-loaded gel formulations exhibited a sustained drug release manner in vitro, regardless of CL/GA ratios. The specimen with a powder form in the bulk state, a stable aqueous solution before heating and an appropriate degradation rate in vivo was selected as the optimal carrier to evaluate the in vivo efficacy. A single injection of the optimal gel formulation showed a remarkable hypoglycemic efficacy up to one week in diabetic db/db mice. Furthermore, three successive administrations of this gel formulation within one month significantly lowered glycosylated hemoglobin and protected islets of db/db mice. As a result, a promising once-weekly delivery system of Lira was developed, which not only afforded long-term glycemic control but also significantly improved patient compliance.
Stimuli-sensitive injectable polymeric hydrogels are one of the promising delivery vehicles for the controlled release of bioactive agents. In aqueous solutions, these polymers are able to switch sol-to-gel transitions in response to various stimuli including pH, temperature, light, enzyme and magnetic field. Therapeutic agents, including chemotherapeutic agents, protein drugs or cells, are easily mixed with the low-viscous polymer solution at room temperature. Therapeutic-agents-containing solutions are readily injected into target sites through syringe or catheter, which could form hydrogel depot and serve as bioactive molecules release carriers. In particular, they are convenient for in vivo injection in a minimally invasive manner. Owing to their ease of handling, hydrogel scaffolds encapsulated with a wide array of therapeutic agents including growth factors, cells or fillers have been used in regeneration or filling of the defect area. Therefore, injectable hydrogels found a variety of biomedical applications, such as drug delivery and tissue engineering. Here, we summarize the chemical designs and recent developments of polysaccharide-based injectable hydrogels, giving a special attention to hydrogels prepared using amphiphilic polysaccharides for biomedical applications. Advantages and future perspectives of polysaccharide-based injectable hydrogels are highlighted.
In this study, a new pH-/temperature-sensitive, biocompatible, biodegradable, and injectable hydrogel based on poly(ethylene glycol)-poly(amino carbonate urethane) (PEG-PACU) copolymers has been developed for the sustained delivery of human growth hormone (hGH). In aqueous solutions, PEG-PACU-based copolymers existed as sols at low pH and temperature (pH 6.0, 23 °C), whereas they formed gels in the physiological condition (pH 7.4, 37 °C). The physicochemical characteristics, including gelation rate, mechanical strength and viscosity, of the PEG-PACU hydrogels could be finely tuned by varying the polymer weight, pH and temperature of the copolymer. An in vivo injectable study in the back of Sprague-Dawley (SD) rats indicated that the copolymer could form an in situ gel, which exhibited a homogenous porous structure. In addition, an in vivo biodegradation study of the PEG-PACU hydrogels showed controlled degradation of the gel matrix without inflammation at the injection site and the surrounding tissue. The hGH-loaded PEG-PACU copolymer solution readily formed a hydrogel in SD rats, which subsequently inhibited the initial hGH burst and led to the sustained release of hGH. Overall, the PEG-PACU-based copolymers prepared in this study are expected to be useful biomaterials for the sustained delivery of hGH.
Nanobiohybrid hydrogels, which are composed of inorganic nanoparticles and biodegradable polymeric
hydrogels, have received special attention in the field of drug and protein delivery. These systems exploit
the unique advantages of each component to improve the efficacy of the therapeutic agents and
minimize undesirable side effects. The objective of this study was to develop a gemcitabine-loaded
nanobiohybrid hydrogel to overcome the limitations of this anticancer drug, such as the very short halflife
of gemcitabine (GEM) in plasma, the systemic toxicity from high-dose therapy, and the need for
repeated administration during treatment. The proposed injectable nanobiohybrid hydrogel for
controlled release of GEM was prepared through intercalation and adsorption of GEM to interlayer
galleries and surfaces of montmorillonite (MMT) nanoparticles (forming MMT–GEM complexes), followed
by the dispersion of the MMT–GEM complexes into the injectable, biodegradable, temperature-sensitive
poly(3-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(3-caprolactone-co-lactide) hydrogel.
The MMT–GEM complex and the nanobiohybrid hydrogel were characterized by X-ray diffraction
analysis, particle size and zeta potential measurements, Fourier transform infrared spectroscopy, and
scanning electron microscopy. Improvements in the properties of nanobiohybrid hydrogel in comparison
with the pristine hydrogel were confirmed through sol–gel phase transition diagram, rheological
measurement, and in vivo stability. The non-cytotoxicity of the nanobiohybrid hydrogel was proven by
MTT assay using the 293T cell line. Compared with the pristine hydrogel, the in vitro GEM release from
the nanobiohybrid hydrogel showed a considerably prolonged GEM release time and a much lower initial
burst. The antitumor efficacy studies on pancreatic tumor-bearing mice revealed a significant inhibition
of tumor growth. Hence, these findings demonstrate that the nanobiohybrid hydrogel is a desirable
carrier for controlled release of GEM in the treatment of pancreatic cancer.
Introduction
Pancreatic cancer is one of the most deadly types of cancer, with
over 250 000 deaths annually, and the 5 year survival rate of
patients is no more than 5%.1–3 The treatment options
including surgery, chemotherapy, and radiation remain modest
in efficacy. Chemotherapy is the optimal choice for nonresectable
cancer or cancer in metastatic stage to improve the
survival of patients.4,5
Gemcitabine (20,20-diuoro-20-deoxycytidine, GEM), an anticancer
drug, has been demonstrated to be highly effective for
acting against
In this review we intend to provide a relatively comprehensive summary of the work of supramolecular hydrogelators after 2004 and to put emphasis particularly on the applications of supramolecular hydrogels/hydrogelators as molecular biomaterials. After a brief introduction of methods for generating supramolecular hydrogels, we discuss supramolecular hydrogelators on the basis of their categories, such as small organic molecules, coordination complexes, peptides, nucleobases, and saccharides. Following molecular design, we focus on various potential applications of supramolecular hydrogels as molecular biomaterials, classified by their applications in cell cultures, tissue engineering, cell behavior, imaging, and unique applications of hydrogelators. Particularly, we discuss the applications of supramolecular hydrogelators after they form supramolecular assemblies but prior to reaching the critical gelation concentration because this subject is less explored but may hold equally great promise for helping address fundamental questions about the mechanisms or the consequences of the self-assembly of molecules, including low molecular weight ones. Finally, we provide a perspective on supramolecular hydrogelators. We hope that this review will serve as an updated introduction and reference for researchers who are interested in exploring supramolecular hydrogelators as molecular biomaterials for addressing the societal needs at various frontiers.
Localized cancer treatments with combination drugs have recently emerged as crucial approaches for effective inhibition of tumor growth and reoccurrence. In this study, we present a new strategy for the osteosarcoma treatment by localized co-delivery of multiple drugs, including doxorubicin (DOX), cisplatin (CDDP) and methotraxate (MTX), using thermosensitive PLGA-PEG-PLGA hydrogels. The release profiles of the drugs from the hydrogels were investigated in vitro. It was found that the multi-drug co-loaded hydrogels exhibited synergistic effects on cytotoxicity against osteosarcoma Saos-2 and MG-63 cells in vitro. After a single peritumoral injection of the drug-loaded hydrogels into nude mice bearing human osteosarcoma Saos-2 xenografts, the hydrogels co-loaded with DOX, CDDP and MTX displayed the highest tumor suppression efficacy in vivo for up to 16 days, as well as led to enhanced tumor apoptosis and increased regulation of the expressions of apoptosis-related genes. Moreover, the monitoring on the mice body change and the ex vivo histological analysis of the key organs indicated that the localized treatments caused less systemic toxicity and no obvious damage to the normal organs. Therefore, the approach of localized co-delivery of DOX, CDDP and MTX by the thermosensitive hydrogels may be a promising approach for enhanced osteosarcoma treatment.
The discovery of RNAi in the late 1990s unlocked a new realm of therapeutic possibilities by enabling potent and specific silencing of theoretically any desired genetic target. Better elucidation of the mechanism of action, the impact of chemical modifications that stabilize and reduce nonspecific effects of siRNA molecules, and the key design considerations for effective delivery systems has spurred progress toward developing clinically-successful siRNA therapies. A logical aim for initial siRNA translation is local therapies, as delivering siRNA directly to its site of action helps to ensure that a sufficient dose reaches the target tissue, lessens the potential for off-target side effects, and circumvents the substantial systemic delivery barriers. While locally injected or topically applied siRNA has progressed into numerous clinical trials, an enormous opportunity exists to develop sustained-release, local delivery systems that enable both spatial and temporal control of gene silencing. This review focuses on material platforms that establish both localized and controlled gene silencing, with emphasis on the systems that show most promise for clinical translation.
Statement of significance:
Hypoxia occurs in a variety of pathological conditions including stroke, rheumatoid arthritis, atherosclerosis, and tumors. In this study, we developed a novel type of hypoxia-sensitive polymeric micelles (HS-PMs) that can specifically release the drug under the hypoxic conditions. HS-PMs were prepared using poly(ethylene glycol) as the hydrophilic block and poly(ε-(4-nitro)benzyloxycarbonyl-l-lysine) as the hydrophobic block. Owing to its amphiphilic nature, the block copolymer formed micelles and encapsulated doxorubicin (DOX) in an aqueous condition. The DOX-loaded micelles exhibited rapid intracellular release of DOX under the hypoxic condition. Overall, it is evident that the HS-PMs prepared in this study have the potential to effectively deliver hydrophobic drugs into the hypoxic cells involved in various intractable diseases.
An injectable, self-healing hydrogel (≈1.5 kPa) is developed for healing nerve system deficits. Neurosphere-like progenitors proliferate in the hydrogel and differentiate into neuron-like cells. In the zebrafish injury model, the central nervous system function is partially rescued by injection of the hydrogel and significantly rescued by injection of the neurosphere-laden hydrogel. The self-healing hydrogel may thus potentially repair the central nervous system.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
The use of nanoparticulate pharmaceutical drug delivery systems (NDDSs) to enhance the in vivo effectiveness of drugs is now well established. The development of multifunctional and stimulus-sensitive NDDSs is an active area of current research. Such NDDSs can have long circulation times, target the site of the disease and enhance the intracellular delivery of a drug. This type of NDDS can also respond to local stimuli that are characteristic of the pathological site by, for example, releasing an entrapped drug or shedding a protective coating, thus facilitating the interaction between drug-loaded nanocarriers and target cells or tissues. In addition, imaging contrast moieties can be attached to these carriers to track their real-time biodistribution and accumulation in target cells or tissues. Here, I highlight recent developments with multifunctional and stimuli-sensitive NDDSs and their therapeutic potential for diseases including cancer, cardiovascular diseases and infectious diseases.
The aim of this research is using multi-sensitive polymers to prepare injectable hydrogels for controlled protein/drug delivery. A series of biodegradable multi-sensitive poly(ether urethane)s were prepared through a simple one-pot condensation of poly(ethylene glycol), 2, 2'-dithiodiethanol, N-methyldiethanolamine and hexamethylene diisocyanate. The sol-gel phase transition behaviors of the obtained copolymers were investigated. The results showed that the aqueous media of the multi-segment copolymers changed from a sol-to-gel phase transition with increasing temperature and pH. At a certain concentration, the copolymer solution could immediately change to a gel under physiological conditions at 37 ℃ and pH 7.4, and could be employed as in situ injectable hydrogels in vivo. Insulin was used as a model protein drug for the evaluation of the injectable hydrogels using as a site-specific drug delivery system. As a result, the release of insulin from the hydrogel devices can be controlled by degradation of the copolymer, which is modulated via the 2, 2'-dithiodiethanol content in the poly(ether-urethane)s. These properties of the hydrogels may prove to be a promising candidate for the injectable and controllable protein drug delivery device.
The lack of vascularization within tissue-engineered constructs remains the primary cause of construct failure following implantation. Porous constructs have been successful in allowing for vessel infiltration without requiring extensive matrix degradation. We hypothesized that the rate and maturity of infiltrating vessels could be enhanced by complementing the open pore structure with the added delivery of DNA encoding for angiogenic growth factors. Both 100 and 60 μm porous and non-porous hyaluronic acid hydrogels loaded with pro-angiogenic (pVEGF) or reporter (pGFPluc) plasmid nanoparticles were used to study the effects of pore size and DNA delivery on angiogenesis in a mouse subcutaneous implant model. GFP-expressing transfected cells were found inside all control hydrogels over the course of the study, although transfection levels peaked by week 3 for 100 and 60 μm porous hydrogels. Transfection in non-porous hydrogels continued to increase over time corresponding with continued surface degradation. pVEGF transfection levels were not high enough to enhance angiogenesis by increasing vessel density, maturity, or size, although by 6 weeks for all pore size hydrogels more hydrogel implants were positive for vascularization when pVEGF polyplexes were incorporated compared to control hydrogels. Pore size was found to be the dominant factor in determining the angiogenic response with 60 μm porous hydrogels having more vessels/area present than 100 μm porous hydrogels at the initial onset of angiogenesis at 3 weeks. The results of this study show promise for the use of polyplex loaded porous hydrogels to transfect infiltrating cells in vivo and guide tissue regeneration and repair.
This study is aimed to develop a long-acting injectable formulation in treatment of type II diabetes. A glucoregulatory polypeptide, exenatide (EXT), was chosen as the model drug, and an aqueous block copolymer system with a sol-gel transition upon the increase of temperature was selected as the delivery matrix of EXT. The thermoreversible hydrogel composed of poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was found to slower the degradation of the polypeptide to a large extent. However, the initial formulation in this study exhibited a significant drug burst effect, which is a common problem to load a hydrophilic small or medium-size polypeptide into a hydrogel. Zinc acetate was then introduced to slow down the EXT release by formation of insoluble Zn-EXT complexes in the thermogel matrix. Yet an incomplete release became another crucial problem, which is also common for peptide and protein delivery. The synergistic effect of three excipients (zinc acetate, PEG, and sucrose) under an appropriate condition overcame these two problems simultaneously, and the sustained release of drug lasted for 1 week. In vivo experiments via mice oral glucose tolerance tests demonstrated an improved glucose tolerance for 1 week after a single subcutaneous injection of the optimal EXT formulation. As a result, a formulation of antidiabetic drugs was set up, and meanwhile a strategy using synergistic excipients to adjust release profiles of peptides from hydrogels was put forward.
A cyclodextrin-based supramolecular hydrogel system with supramolecularly anchored active cationic copolymer/plasmid DNA (pDNA) polyplexes was studied as a sustained gene delivery carrier. A few biodegradable triblock copolymers of methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly[2-(dimethylamino)ethyl methacrylate] (MPEG-PCL-PDMAEMA) with well-defined cationic block lengths were prepared to condense pDNA. The MPEG-PCL-PDMAEMA copolymers exhibit good ability to condense pDNA into 275-405 nm polyplexes with hydrophilic MPEG in the outer corona. The MPEG corona imparted greater stability to the pDNA polyplexes and also served as an anchoring segment when the pDNA polyplexes were encapsulated in α-CD-based supramolecular polypseudorotaxane hydrogels. More interestingly, the resultant hydrogels were able to sustain release of pDNA up to 6 days. The pDNA was released in the form of polyplex nanoparticles as it was bound electrostatically to the cationic segment of the MPEG-PCL-PDMAEMA copolymers. The bioactivity of the released pDNA polyplexes at various durations was further investigated. Protein expression level of pDNA polyplexes released over the durations was comparable to that of freshly prepared PEI polyplexes. Being thixotropic and easily prepared without using organic solvent, this supramolecular in situ gelling system has immense potential as an injectable carrier for sustained gene delivery.
Enhancing human mesenchymal stem cell (hMSC) differentiation via RNA interference (RNAi) could provide an effective way of controlling cell fate for tissue engineering, but a safe and effective delivery vehicle must first be developed. Here, we evaluated an array of synthetic end-modified poly(beta-amino ester) (PBAE)-based nanoparticles to optimize siRNA delivery into hMSCs. In general, cystamine-terminated polymers caused the most knockdown, with the best polymer achieving 91% knockdown 20 days post-transfection. Binding studies revealed that the cystamine-terminated polymer bound siRNA tightly at lower weight ratios of polymer to siRNA but then efficiently released siRNA upon exposure to a reducing environment, suggesting that this class of PBAEs can form tight initial interactions with its cargo and then cause efficient, environmentally-triggered release in the cytoplasm. Finally, we tested a functional application of this system by transfecting hMSCs with siRNA against an inhibitor of osteogenesis, B-cell lymphoma (Bcl)-like protein 2 (BCL2L2). This resulted in enhanced osteogenesis over 4 weeks as evidenced by Alizarin Red S staining and calcium quantification. The bioreducible PBAE/siRNA nanoparticles developed here can provide a means of safe and effective control of hMSC differentiation for a wide variety of applications.
Aqueous solutions that undergo sol-to-gel transition as the temperature increases have been extensively studied during the last decade. The material can be designed by controlling the hydrophilic and hydrophobic balance of the material. Basically, the molecular weight of the hydrophilic block and hydrophobic block of a compound should be fine-tuned from the synthetic point of view. In addition, stereochemistry, microsequence, topology, and nanostructures of the compound also affect the transition temperature, gel window, phase diagram, and modulus of the gel. From a practical point of view, biodegradability, biocompatibility, and interactions between the material and drug or cell should be considered in designing a thermogelling material. The interactions are particularly important in that they control drug release profile and initial burst release of the drug in the drug delivery system, and affect cell proliferation, differentiation, and biomarker expression in three-dimensional cell culture and tissue engineering application. This review provides an in-depth summary of the recent progress of thermogelling systems including polymers, low molecular compounds, and nanoemulsions. Their biomedical applications were also comparatively discussed. In addition, perspectives on future material design of a new thermogelling material and its application are suggested.
Here, we describe a concept for localized and long-term delivery of short interfering RNA (siRNA) using an injectable polyplex hydrogel possessing thermosensitivity and biodegradability properties. We prepared a low molecular weight polyethyleneimine-poly(organophosphazene) conjugate as a thermosensitive and cationic polymer that has a cleavable ester linkage. The conjugates formed about 100 nm sized polyplexes with siRNAs, and the polyplex solution turned into a polyplex hydrogel at body temperature via a hydrophobic interaction. We injected the polyplex hydrogel with siRNA of cyclin B1, an essential protein for controlling the cell cycle, into the tumor xenograft model. Polyplexes were slowly released from the polyplex hydrogel by dissolution and degradation, allowing an in vivo antitumor effect via cyclin B1 gene silencing for 4 weeks with only a single injection.
A study was conducted to demonstrate the use of injectable polymeric delivery systems for the controlled release of pharmaceutical proteins, with specific focus on hydrogels. The study covered injectable systems based on nano- and particularly microparticles, along with physical and chemical cross-linking methods used for in situ gelling systems and environmentally responsive hydrogels and their use for protein release. Nanoparticle and microsphere-based drug delivery systems had advantages due to their injectability and the possibility to achieve prolonged release. Hydrogels were specifically used for controlled release of pharmaceutical proteins, as they were cross-linked networks of hydrophilic polymers capable of retaining large amounts of water while remaining insoluble and maintaining their three-dimensional structure. The hydrogel precursors were synthesized by reacting dihydroxy polyethylene glycol with D,L-lactide using stannous octoate as a catalyst.
Injectable hydrogels with biodegradability have in situ formability which in vitro/in vivo allows an effective and homogeneous encapsulation of drugs/cells, and convenient in vivo surgical operation in a minimally invasive way, causing smaller scar size and less pain for patients. Therefore, they have found a variety of biomedical applications, such as drug delivery, cell encapsulation, and tissue engineering. This critical review systematically summarizes the recent progresses on biodegradable and injectable hydrogels fabricated from natural polymers (chitosan, hyaluronic acid, alginates, gelatin, heparin, chondroitin sulfate, etc.) and biodegradable synthetic polymers (polypeptides, polyesters, polyphosphazenes, etc.). The review includes the novel naturally based hydrogels with high potential for biomedical applications developed in the past five years which integrate the excellent biocompatibility of natural polymers/synthetic polypeptides with structural controllability via chemical modification. The gelation and biodegradation which are two key factors to affect the cell fate or drug delivery are highlighted. A brief outlook on the future of injectable and biodegradable hydrogels is also presented (326 references).
Poly(ethylene glycol)-b-poly(γ-benzyl L-glutamate)s bearing the disulfide bond (PEG-SS-PBLGs), which is specifically cleavable in intracellular compartments, were prepared via a facile synthetic route as a potential carrier of camptothecin (CPT). Diblock copolymers with different lengths of PBLG were synthesized by ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of a PEG macroinitiator (PEG-SS-NH(2)). Owing to their amphiphilic nature, the copolymers formed spherical micelles in an aqueous condition, and their particle sizes (20-125 nm in diameter) were dependent on the block length of PBLG. Critical micelle concentrations of the copolymers were in the range 0.005-0.065 mg/mL, which decreased as the block length of PBLG increased. CPT, chosen as a model anticancer drug, was effectively encapsulated up to 12 wt % into the hydrophobic core of the micelles by the solvent casting method. It was demonstrated by the in vitro optical imaging technique that the fluorescence signal of doxorubicin, quenched in the PEG-SS-PBLG micelles, was highly recovered in the presence of glutathione (GSH), a tripeptide reducing disulfide bonds in the cytoplasm. The micelles released CPT completely within 20 h under 10 mM GSH, whereas only 40% of CPT was released from the micelles in the absence of GSH. From the in vitro cytotoxicity test, it was found that CPT-loaded PEG-SS-PBLG micelles showed higher toxicity to SCC7 cancer cells than CPT-loaded PEG-b-PBLG micelles without the disulfide bond. Microscopic observation demonstrated that the disulfide-containing micelle could effectively deliver the drug into nuclei of SCC7 cells. These results suggest that PEG-SS-PBLG diblock copolymer is a promising carrier for intracellular delivery of CPT.
A concentrated fish soup could be gelled in the winter and re-solled upon heating. In contrast, some synthetic copolymers exhibit an inverse sol-gel transition with spontaneous physical gelation upon heating instead of cooling. If the transition in water takes place below the body temperature and the chemicals are biocompatible and biodegradable, such gelling behavior makes the associated physical gels injectable biomaterials with unique applications in drug delivery and tissue engineering etc. Various therapeutic agents or cells can be entrapped in situ and form a depot merely by a syringe injection of their aqueous solutions at target sites with minimal invasiveness and pain. This tutorial review summarizes and comments on this soft matter, especially thermogelling poly(ethylene glycol)-(biodegradable polyester) block copolymers. The main types of injectable hydrogels are also briefly introduced, including both physical gels and chemical gels.
Local delivery of DNA through a hydrogel scaffold would increase the applicability of gene therapy in tissue regeneration and cancer therapy. However, the delivery of DNA/cationic polymer nanoparticles (polyplexes) using hydrogels is challenging due to the aggregation and inactivation of polyplexes during their incorporation into hydrogel scaffolds. We developed a novel process (termed caged nanoparticle encapsulation or CnE) to load concentrated and unaggregated non-viral gene delivery nanoparticles into various hydrogels. Previously, we showed that PEG hydrogels loaded with DNA/PEI polyplexes through this process were able to deliver genes both in vitro and in vivo. In this study, we found that hyaluronic acid and fibrin hydrogels with concentrated and unaggregated polyplexes loaded through CnE were able to deliver genes in vivo as well, demonstrating the universality of the process.
Small interfering RNAs (siRNAs) are able to silence their target genes when they are successfully delivered intact into the cytoplasm. Delivery systems that enhance siRNA localization to the cytoplasm can facilitate gene silencing by siRNA therapeutics. We describe an arginine-conjugated poly(cystaminebisacrylamide-diaminohexane) (poly(CBA-DAH-R)), a bioreducible cationic polymer, as an siRNA carrier for therapeutic gene silencing for cancer. After intracellular uptake of the siRNA/poly(CBA-DAH-R) polyplexes, the reductive environment of the cytoplasm cleaves the disulfide linkages in the polymeric backbone, resulting in decomplexing of the siRNA/poly(CBA-DAH-R) polyplexes and release of siRNA molecules throughout the cytoplasm. The siRNA/poly(CBA-DAH-R) polyplexes, which demonstrate increased membrane permeability with arginine modification, have a similar level of cellular uptake as siRNA/bPEI polyplexes. The VEGF siRNA/poly(CBA-DAH-R) polyplexes, however, inhibit VEGF expression to a greater degree than VEGF siRNA/bPEI in various human cancer cell lines. The improved RNAi activity demonstrated by the VEGF siRNA/poly(CBA-DAH-R) polyplexes is due to enhanced intracellular delivery and effective localization to the cytoplasm of the VEGF siRNAs. These results demonstrate that the VEGF siRNA/poly(CBA-DAH-R) polyplex delivery system may useful for siRNA-based approaches for cancer therapy.
The applications of a wide range of hydrogels in tissue engineering were presented. The design parameters of hydrogels required for them to be useful, regardless of their origin from natural resources or synthetic creation were discussed. The use of polymers in promoting blood vessel network formation in the tissue was described. The problems encountered in the design and engineering of various sequences of polypeptides with known functions were also studied.
Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally--a challenge that has been successfully addressed.