Physical Double‐Network Hydrogel Adhesives with Rapid Shape Adaptability,Fast Self‐Healing,Antioxidant and NIR/pH Stimulus‐Responsiveness for Multidrug‐Resistant Bacterial Infection and Removable Wound Dressing

Developing physical double‐network (DN) removable hydrogel adhesives with both high healing efficiency and photothermal antibacterial activities to cope with multidrug‐resistant bacterial infection, wound closure, and wound healing remains an ongoing challenge. An injectable physical DN self‐healing hydrogel adhesive under physiological conditions is designed to treat multidrug‐resistant bacteria infection and full‐thickness skin incision/defect repair. The hydrogel adhesive consists of catechol–Fe³⁺ coordination cross‐linked poly(glycerol sebacate)‐co‐poly(ethylene glycol)‐g‐catechol and quadruple hydrogen bonding cross‐linked ureido‐pyrimidinone modified gelatin. It possesses excellent anti‐oxidation, NIR/pH responsiveness, and shape adaptation. Additionally, the hydrogel presents rapid self‐healing, good tissue adhesion, degradability, photothermal antibacterial activity, and NIR irradiation and/or acidic solution washing‐assisted removability. In vivo experiments prove that the hydrogels have good hemostasis of skin trauma and high killing ratio for methicillin‐resistant staphylococcus aureus (MRSA) and achieve better wound closure and healing of skin incision than medical glue and surgical suture. In particular, they can significantly promote full‐thickness skin defect wound healing by regulating inflammation, accelerating collagen deposition, promoting granulation tissue formation, and vascularization. These on‐demand dissolvable and antioxidant physical double‐network hydrogel adhesives are excellent multifunctional dressings for treating in vivo MRSA infection, wound closure, and wound healing.     

Multifunctional Injectable Hydrogel Dressings for Effectively Accelerating Wound Healing: Enhancing Biomineralization Strategy

Bacterial infection can cause chronic nonhealing wounds, which may be a great threat to public health. It is highly desirable to develop an injectable wound dressing hydrogel with multifunctions including self-healing, remodeling, antibacterial, radical scavenging ability, and excellent photothermal properties to promote the regeneration of damaged tissues in clinical practice. In this work, dopamine-modified gelatin (Gel-DA) is employed for the first time as a biotemplate for enhancing the biomineralization ability of gelatin to synthesize dopamine-modified gelatin@Ag nanoparticles (Gel-DA@Ag NPs). Further, the prepared Gel-DA@Ag NPs with antioxidant activity and near-infrared (NIR) laser irradiation synergistic antibacterial behavior are fixed in the guar gum based hydrogels through the formation of borate/didiol bonds to possess remolding, injectable, and self-healing performance. In addition, the multifunctional hydrogels can completely cover the irregular wound shape to prevent secondary injury. More importantly, these hydrogel platforms under NIR can significantly accelerate wound healing with more skin appendages like hair follicles and blood vessels appearing. Therefore, it is expected that these hydrogels can serve as competitive multifunctional dressings in biomedical field, including bacteria-derived wound infection and other tissue repair related to reactive oxygen species overexpression.     

Tissue Tapes—Phenolic Hyaluronic Acid Hydrogel Patches for Off‐the‐Shelf Therapy

Hydrogels have been applied to improve stem cell therapy and drug delivery, but current hydrogel‐based delivery methods are inefficient in clinical settings due to difficulty in handling and treatment processes, and low off‐the‐shelf availability. To overcome these limitations, an adhesive hyaluronic acid (HA) hydrogel patch is developed that acts as a ready‐to‐use tissue tape for therapeutic application. The HA hydrogel patches functionalized with phenolic moieties (e.g., catechol, pyrogallol) exhibit stronger tissue adhesiveness, greater elastic modulus, and increased off‐the‐shelf availability, compared with their bulk solution gel form. With this strategy, stem cells are efficiently engrafted onto beating ischemic hearts without injection, resulting in enhanced angiogenesis in ischemic regions and improving cardiac functions. HA hydrogel patches facilitate the in vivo engraftment of stem cell–derived organoids. The off‐the‐shelf availability of the hydrogel patch is also demonstrated as a drug‐loaded ready‐made tissue tape for topical drug delivery to promote wound healing. Importantly, the applicability of the cross‐linker‐free HA patch is validated for therapeutic cell and drug delivery. The study suggests that bioinspired phenolic adhesive hydrogel patches can provide an innovative method for simple but highly effective cell and drug delivery, increasing the off‐the‐shelf availability—a critically important component for translation to clinical settings.     

Injectable Self‐Healing Antibacterial Bioactive Polypeptide‐Based Hybrid Nanosystems for Efficiently Treating Multidrug Resistant Infection,Skin‐Tumor Therapy,and Enhancing Wound Healing

The surgical procedure in skin‐tumor therapy usually results in cutaneous defects, and multidrug‐resistant bacterial infection could cause chronic wounds. Here, for the first time, an injectable self‐healing antibacterial bioactive polypeptide‐based hybrid nanosystem is developed for treating multidrug resistant infection, skin‐tumor therapy, and wound healing. The multifunctional hydrogel is successfully prepared through incorporating monodispersed polydopamine functionalized bioactive glass nanoparticles (BGN@PDA) into an antibacterial F127‐ε‐Poly‐L‐lysine hydrogel. The nanocomposites hydrogel displays excellent self‐healing and injectable ability, as well as robust antibacterial activity, especially against multidrug‐resistant bacteria in vitro and in vivo. The nanocomposites hydrogel also demonstrates outstanding photothermal performance with (near‐infrared laser irradiation) NIR irradiation, which could effectively kill the tumor cell (>90%) and inhibit tumor growth (inhibition rate up to 94%) in a subcutaneous skin‐tumor model. In addition, the nanocomposites hydrogel effectively accelerates wound healing in vivo. These results suggest that the BGN‐based nanocomposite hydrogel is a promising candidate for skin‐tumor therapy, wound healing, and anti‐infection. This work may offer a facile strategy to prepare multifunctional bioactive hydrogels for simultaneous tumor therapy, tissue regeneration, and anti‐infection.     

Covalently Adaptable Elastin‐Like Protein–Hyaluronic Acid (ELP–HA) Hybrid Hydrogels with Secondary Thermoresponsive Crosslinking for Injectable Stem Cell Delivery

Shear‐thinning, self‐healing hydrogels are promising vehicles for therapeutic cargo delivery due to their ability to be injected using minimally invasive surgical procedures. An injectable hydrogel using a novel combination of dynamic covalent crosslinking with thermoresponsive engineered proteins is presented. Ex situ at room temperature, rapid gelation occurs through dynamic covalent hydrazone bonds by simply mixing two components: hydrazine‐modified elastin‐like protein (ELP) and aldehyde‐modified hyaluronic acid. This hydrogel provides significant mechanical protection to encapsulated human mesenchymal stem cells during syringe needle injection and rapidly recovers after injection to retain the cells homogeneously within a 3D environment. In situ, the ELP undergoes a thermal phase transition, as confirmed by coherent anti‐Stokes Raman scattering microscopy observation of dense ELP thermal aggregates. The formation of the secondary network reinforces the hydrogel and results in a tenfold slower erosion rate compared to a control hydrogel without secondary thermal crosslinking. This improved structural integrity enables cell culture for three weeks postinjection, and encapsulated cells maintain their ability to differentiate into multiple lineages, including chondrogenic, adipogenic, and osteogenic cell types. Together, these data demonstrate the promising potential of ELP–HA hydrogels for injectable stem cell transplantation and tissue regeneration.     

Bioinspired Multifunctional Hybrid Hydrogel Promotes Wound Healing

Inspired by the coordinated multiple healing mechanism of the organism, a four‐armed benzaldehyde‐terminated polyethylene glycol and dodecyl‐modified chitosan hybrid hydrogel with vascular endothelial growth factor (VEGF) encapsulation are presented for efficient and versatile wound healing. The hybrid hydrogel is formed through the reversible Schiff base and possesses self‐healing capability. As the dodecyl tails can insert themselves into and be anchored onto the lipid bilayer of the cell membrane, the hybrid hydrogel has outstanding tissue adhesion, blood cell coagulation and hemostasis, anti‐infection, and cell recruitment functions. Moreover, by loading in and controllably releasing VEGF from the hybrid hydrogel, the processes of cell proliferation and tissue remodeling in the wound bed can be significantly improved. Based on an in vivo study of the multifunctional hybrid hydrogel, it is demonstrated that acute tissue injuries such as vessel bleeding and liver bleeding can be repaired immediately because of the outstanding adhesion and hemostasis features of the hydrogel. Moreover, the chronic wound‐healing process of an infectious full‐thickness skin defect model can also be significantly enhanced by promoting angiogenesis, collagen deposition, macrophage polarization, and granulation tissue formation. Thus, this multifunctional hybrid hydrogel is potentially valuable for clinical applications.     

Injectable Hydrogels with In Situ Double Network Formation Enhance Retention of Transplanted Stem Cells

Stem cell transplantation via direct injection is a minimally invasive strategy being explored for treatment of a variety of injuries and diseases. Injectable hydrogels with shear moduli <50 Pa can mechanically protect cells during the injection process; however, these weak gels typically biodegrade within 1–2 weeks, which may be too fast for many therapeutic applications. To address this limitation, an injectable hydrogel is designed that undergoes two different physical crosslinking mechanisms. The first crosslinking step occurs ex vivo through peptide‐based molecular recognition to encapsulate cells within a weak gel that provides mechanical protection from injection forces. The second crosslinking step occurs in situ to form a reinforcing network that significantly retards material biodegradation and prolongs cell retention time. Human adipose‐derived stem cells are transplanted into the subcutaneous space of a murine model using hand‐injection through a 28‐gauge syringe needle. Cells delivered within the double‐network hydrogel are significantly protected from mechanical damage and have significantly enhanced in vivo cell retention rates compared to delivery within saline and single network hydrogels. These results demonstrate that in situ formation of a reinforcing network within an already existing hydrogel can greatly improve transplanted cell retention, thereby enhancing potential regenerative medicine therapies.     

Regulation of Stem Cell Fate in a Three‐Dimensional Micropatterned Dual‐Crosslinked Hydrogel System

Micropatterning technology is a powerful tool for controlling the cellular microenvironment and investigating the effects of physical parameters on cell behaviors, such as migration, proliferation, apoptosis, and differentiation. Although there have been significant developments in regulating the spatial and temporal distribution of physical properties in various materials, little is known about the role of the size of micropatterned regions of hydrogels with different crosslinking densities on the response of encapsulated cells. In this study, a novel alginate hydrogel system that can be micropatterned three‐dimensionally is engineered to create regions that are crosslinked by a single mechanism or dual mechanisms. By manipulating micropattern size while keeping the overall ratio of single‐ to dual‐crosslinked hydrogel volume constant, the physical properties of the micropatterned alginate hydrogels are spatially tunable. When human adipose‐derived stem cells (hASCs) are photoencapsulated within micropatterned hydrogels, their proliferation rate is a function of micropattern size. Additionally, micropattern size dictates the extent of osteogenic and chondrogenic differentiation of photoencapsulated hASC. The size of 3D micropatterned physical properties in this new hydrogel system introduces a new design parameter for regulating various cellular behaviors, and this dual‐crosslinked hydrogel system provides a new platform for studying proliferation and differentiation of stem cells in a spatially controlled manner for tissue engineering and regenerative medicine applications.     

Mussel‐Inspired Contact‐Active Antibacterial Hydrogel with High Cell Affinity,Toughness, and Recoverability

Antibacterial hydrogel has received extensive attention in soft tissue repair, especially preventing infections those associated with impaired wound healing. However, it is challenging in developing an inherent antibacterial hydrogel integrating with excellent cell affinity and superior mechanical properties. Inspired by the mussel adhesion chemistry, a contact‐active antibacterial hydrogel is proposed by copolymerization of methacrylamide dopamine (MADA) and 2‐(dimethylamino)ethyl methacrylate and forming an interpenetrated network with quaternized chitosan. The reactive catechol groups of MADA endow the hydrogel with contact intensified bactericidal activity, because it increases the exposure of bacterial cells to the positively charged groups of the hydrogel and strengthens the bactericidal effect. MADA also maintains the good adhesion of fibroblasts to the hydrogel. Moreover, the hybrid chemical and physical cross‐links inner the hydrogel network makes the hydrogel strong and tough with good recoverability. In vitro and in vivo tests demonstrate that this tough and contact‐active antibacterial hydrogel is a promising material to fulfill the dual functions of promoting tissue regeneration and preventing bacterial infection for wound‐healing applications.     

Facile Stem Cell Delivery to Bone Grafts Enabled by Smart Shape Recovery and Stiffening of Degradable Synthetic Periosteal Membranes

Delivering stem/progenitor cells via a degradable synthetic membrane to devitalized allogenic tissue graft surfaces presents a promising allograft‐mediated tissue regeneration strategy. However, balancing degradability and bioactivity of the synthetic membrane with physical characteristics demanded for successful clinical translation is challenging. Here, well‐integrated composites of hydroxyapatite (HA) and amphiphilic poly(lactide‐co‐glycolide)‐b‐poly(ethylene glycol)‐b‐poly(lactide‐co‐glycolide) (PELGA) with tunable degradation rates are designed that stiffen upon hydration and exhibit excellent shape recovery ability at body temperature for efficiently delivering skeletal progenitor cells around bone grafts. Unlike conventional degradable polymers that weaken upon wetting, these amphiphilic composites stiffen upon hydration as a result of enhanced polyethylene glycol (PEG) crystallization. HA‐PELGA composite membranes support the attachment, proliferation, and osteogenesis of rat periosteum‐derived cells in vitro, as well as the facile transfer of confluent cell sheets of green fluorescent protein‐labeled bone marrow stromal cells. With efficient shape memory behaviors around physiological temperature, the composite membranes can be programmed with a permanent tubular configuration, deformed into a flat temporary shape desired for cell seeding/cell sheet transfer, and triggered to wrap around a femoral bone allograft upon 37 °C saline rinse and subsequently stiffen. These properties combined make electrospun HA‐PELGA promising smart synthetic periosteal membranes for augmenting allograft healing.     

Injectable Stem Cell‐Laden Photocrosslinkable Microspheres Fabricated Using Microfluidics for Rapid Generation of Osteogenic Tissue Constructs

Direct injection is a minimally invasive method of stem cell transplantation for numerous injuries and diseases. However, despite its promising potential, its clinical translation is difficult due to the low cell retention and engraftment after injection. With high versatility, high‐resolution control and injectability, microfabrication of stem‐cell laden biomedical hydrogels holds great potential as minimally invasive technology. Herein, a strategy of microfluidics‐assisted technology entrapping bone marrow‐derived mesenchymal stem cells (BMSCs) and growth factors in photocrosslinkable gelatin (GelMA) microspheres to ultimately generate injectable osteogenic tissue constructs is presented. Additionally, it is demonstrated that the GelMA microspheres can sustain stem cell viability, support cell spreading inside the microspheres and migration from the interior to the surface as well as enhance cell proliferation. This finding shows that encapsulated cells have the potential to directly and actively participate in the regeneration process. Furthermore, it is found that BMSCs encapsulated in GelMA microspheres show enhanced osteogenesis in vitro and in vivo, associated with a significant increase in mineralization. In short, the proposed strategy can be utilized to facilitate bone regeneration with minimum invasiveness, and can potentially be applied along with other matrices for extended applications.     

Injectable Polypeptide‐Protein Hydrogels for Promoting Infected Wound Healing

Protein is the key composition of all tissues, which has also been widely used in tissue engineering due to its superior biocompatibility and low immunogenicity. However, natural protein usually lacks active functions such as vascularization, osteo‐induction, and neural differentiation, which limits its further applications as a functional biomaterial. Here, based on the mimetic extracellular matrix feature of bovine serum albumin, injectable polypeptide‐protein hydrogels with vascularization and antibacterial abilities are constructed successfully via coordinative cross‐linking of sulfydryl groups with silver ions (Ag+) for the regeneration of infected wound. In this protein hydrogel system, (Ag+), acting as crosslinkers, can not only provide a sterile microenvironment and a strong and robust antibacterial ability but also introduce K₂(SL)₆K₂ (KK) polypeptide, which endows the hydrogel with vascularization behavior. Furthermore, the in vivo data show that the polypeptide‐protein hydrogel has a considerable collagen deposition and vascularization abilities in the early stage of wound healing, resulting in rapid new tissue regeneration featured with newly appeared hair follicles. Altogether, this newly developed multifunctional 3D polypeptide‐protein hydrogel with vascularization, antibacterial properties, and hair follicle promotion can be a promising approach in biomedical fields such as infected wound healing.     

Coordinating Thermogel for Stem Cell Spheroids and Their Cyto‐Effectiveness

A polymer (mP) with thermogelling and metal coordinating properties is prepared by pyridine‐dicarboxylate (PDC) connected poly(ethylene glycol)‐poly(propylene glycol)‐poly(ethylene glycol) triblock copolymers. Tonsil‐derived mesenchymal stem cells (TMSCs) are incorporated in the mP hydrogel by increasing the temperature of the cell‐suspended aqueous mP solution to 37 °C. The TMSCs are randomly embedded in the in situ formed hydrogel at first; however, they aggregated to form live cell spheroids on day 7. In contrast, the spheroid formation is blocked in the Fe³⁺‐incorporating mP thermogel. Compared with the conventional 2D‐cultured stem cells, the stem cell spheroid in the 3D mP culture system exhibits significantly enhanced stemness biomarkers, angiogenic biomarkers, and anti‐inflammatory biomarkers in the growth medium. In addition, the stem cell spheroid exhibits significantly greater biomarker expression for osteogenic, chondrogenic, and adipogenic differentiations than the stem cells cultured in the 2D system in each induction medium. This study suggests that a simple injection of stem cells suspended in the current aqueous mP solution can lead to the spontaneous formation of stem cell spheroids with excellent multipotency and retention in the in situ formed thermogel, and thus opens a direct injectable method for the application of the stem cells at a target site.     

2D and 3D Hybrid Systems for Enhancement of Chondrogenic Differentiation of Tonsil‐Derived Mesenchymal Stem Cells

2D/3D hybrid cell culture systems are constructed by increasing the temperature of the thermogelling poly(ethylene glycol)‐poly(l ‐alanine) diblock copolymer (PEG‐l ‐PA) aqueous solution in which tonsil tissue‐derived mesenchymal stem cells and graphene oxide (GO) or reduced graphene oxide (rGO) are suspended, to 37 °C. The cells exhibit spherical cell morphologies in 2D/3D hybrid culture systems of GO/PEG‐l ‐PA and rGO/PEG‐l ‐PA by using the growth medium. The cell proliferations are 30%–50% higher in the rGO/PEG‐l ‐PA hybrid system than in the GO/PEG‐l ‐PA hybrid system. When chondrogenic culture media enriched with TGF‐β3 is used in the 2D/3D hybrid systems, cells extensively aggregate, and the expression of chondrogenic biomarkers of SOX 9, COL II A1, COL II, and COL X significantly increases in the GO/PEG‐l ‐PA 2D/3D hybrid system as compared with the PEG‐l ‐PA 3D systems and rGO/PEG‐l ‐PA 2D/3D hybrid system, suggesting that the GO/PEG‐l ‐PA 2D/3D hybrid system can be an excellent candidate as a chondrogenic differentiation platform of the stem cell. This paper also suggests that a 2D/3D hybrid system prepared by incorporating 2D materials with various surface biofunctionalities in the in situ forming 3D hydrogel matrix can be a new cell culture system.     

Focal Infection Treatment using Laser‐Mediated Heating of Injectable Silk Hydrogels with Gold Nanoparticles

Medical treatment of subcutaneous bacterial abscesses usually involves systemic high‐dose antibiotics and incision‐drainage of the wound. Such an approach suffers from two main deficiencies: bacterial resistance to antibiotics and pain associated with multiple incision‐drainage‐wound packing procedures. Furthermore, the efficacy of high‐dose systemic antibiotics is limited because of the inability to penetrate into the abscess. To address these obstacles, a treatment relying on laser‐induced heating of gold nanoparticles embedded in an injectable silk‐protein hydrogel is presented. Although bactericidal nanoparticle systems have been previously employed based on silver and nitric oxide, they have limitations regarding customization and safety. The method proposed here is safe and uses biocompatible, highly tunable materials: an injectable silk hydrogel and Au nanoparticles, which are effective absorbers at low laser powers such as those provided by hand‐held devices. A single 10‐minute laser treatment of a subcutaneous infection in mice preserves the general tissue architecture, while achieving a bactericidal effect, even resulting in complete eradication in some cases. The unique materials platform presented can provide the basis for an alternative treatment of focal infections.     

Rapid Generation of Biologically Relevant Hydrogels Containing Long‐Range Chemical Gradients

Many biological processes are regulated by gradients of bioactive chemicals. Thus, the generation of materials with embedded chemical gradients may be beneficial for understanding biological phenomena and generating tissue‐mimetic constructs. Here a simple and versatile method to rapidly generate materials containing centimeter‐long gradients of chemical properties in a microfluidic channel is described. The formation of a chemical gradient is initiated by a passive‐pump‐induced forward flow and further developed during an evaporation‐induced backward flow. The gradient is spatially controlled by the backward flow time and the hydrogel material containing the gradient is synthesized via photopolymerization. Gradients of a cell‐adhesion ligand, Arg‐Gly‐Asp‐Ser (RGDS), are incorporated in poly(ethylene glycol)‐diacrylate (PEG‐DA) hydrogels to test the response of endothelial cells. The cells attach and spread along the hydrogel material in a manner consistent with the RGDS‐gradient profile. A hydrogel containing a PEG‐DA concentration gradient and constant RGDS concentration is also shown. The morphology of cells cultured on such hydrogel changes from round in the lower PEG‐DA concentration regions to well‐spread in the higher PEG‐DA concentration regions. This approach is expected to be a valuable tool to investigate the cell–material interactions in a simple and high‐throughput manner and to design graded biomimetic materials for tissue engineering applications.     

Conjugated Polymer Nanodots as Ultrastable Long‐Term Trackers to Understand Mesenchymal Stem Cell Therapy in Skin Regeneration

Stem cell–based therapies hold great promise in providing desirable solutions for diseases that cannot be effectively cured by conventional therapies. To maximize the therapeutic potentials, advanced cell tracking probes are essential to understand the fate of transplanted stem cells without impairing their properties. Herein, conjugated polymer (CP) nanodots are introduced as noninvasive fluorescent trackers with high brightness and low cytotoxicity for tracking of mesenchymal stem cells (MSCs) to reveal their in vivo behaviors. As compared to the most widely used commercial quantum dot tracker, CP nanodots show significantly better long‐term tracking ability without compromising the features of MSCs in terms of proliferation, migration, differentiation, and secretome. Fluorescence imaging of tissue sections from full‐thickness skin wound–bearing mice transplanted with CP nanodot‐labeled MSCs suggests that paracrine signaling of the MSCs residing in the regenerated dermis is the predominant contribution to promote skin regeneration, accompanied with a small fraction of endothelial differentiation. The promising results indicate that CP nanodots could be used as next generation of fluorescent trackers to reveal the currently ambiguous mechanisms in stem cell therapies through a facile and effective approach.     

Liquid Bandage Harvests Robust Adhesive,Hemostatic, and Antibacterial Performances as a First‐Aid Tissue Adhesive

Massive bleeding and wound infection after tissue trauma are the major dangerous factors of casualties in disasters; hence, first‐aid supplies that can greatly achieve wound closure and effectively control the hemorrhage and infection are urgently needed. Although existing tissue adhesives can adhere to the tissue surfaces and achieve rapid wound closure, most of them have limited hemostatic and antibacterial capacities, making them unsuitable as the first‐aid tissue adhesives. In this study, inspired by the inherent hemostatic and antibacterial capacities of chitosan and the excellent tissue integration capacity originating from a Schiff base reaction, liquid bandage (LBA), an in situ imine crosslinking‐based photoresponsive chitosan hydrogel (NB‐CMC/CMC hydrogel), is developed for emergency wound management. Upon UV irradiation, o‐nitrobenzene in modified carboxymethyl chitosan (CMC) converts to o‐nitrosobenzaldehyde that subsequently crosslinks with amino groups on tissue surface, which endows the LBA with superior tissue adhesive performance. LBA's hemostatic and antibacterial properties can be tuned by the mass ratio of NB‐CMC/CMC. Moreover, it exhibits satisfactory biocompatibility, biodegradability, and the capability to enhance wound healing process. This study sheds new light on the development of a multifunctional hydrogel‐based first‐aid tissue adhesive that can achieve robust tissue adhesion, effectively control bleeding, prevent bacterial infection, and promote wound healing.     

Injectable Hydrogels from Triblock Copolymers of Vitamin E‐Functionalized Polycarbonate and Poly(ethylene glycol) for Subcutaneous Delivery of Antibodies for Cancer Therapy

In this study, ‘ABA’‐type triblock copolymers of vitamin E‐functionalized polycarbonate and poly(ethylene glycol) , i.e., VitE_m‐PEG‐VitE_m, with extremely short hydrophobic block VitE_m, are synthesized and employed to form physically cross‐linked injectable hydrogels for local and sustained delivery of Herceptin. The hydrogels are formed at low concentrations (4–8 wt%). By varying polymer composition and concentration, the rheological behavior, porosity, and drug release properties of hydrogels are readily tunable. The in vitro antitumor specificity and efficacy of Herceptin in hydrogel and solution are investigated by MTT assay against normal and human breast cancer cell lines with different HER2 expression levels. The results demonstrate that the Herceptin‐loaded hydrogel is specific towards HER2‐overexpressing cancer cells and cytotoxic action is comparable to that of the Herceptin solution. The biocompatibility and biodegradability of hydrogel are evaluated in mice with subcutaneous injection by histological examination. It is observed that the hydrogel does not evoke a chronic inflammatory response and degrades within 6 weeks post administration. Biodistribution and anti‐tumor efficacy studies performed in BT474 tumor‐bearing mice show that single subcutaneous injection of Herceptin‐loaded hydrogel at a site close to the tumor enhances the retention of the antibody within the tumor. This leads to superior anti‐tumor efficacy as compared to intravenous (i.v.) and subcutaneous (s.c.) delivery of Herceptin in solution. The tumor size shrank by 77% at Day 28. When the hydrogel is injected at a distal location away from the tumor site, anti‐tumor efficacy is similar to that of weekly i.v. injections of Herceptin solution over 4 weeks, with the number of injections reduced from 4 to 1. These findings suggest that this hydrogel has great potential for use in subcutaneous and sustained delivery of antibodies to increase therapeutic efficacy and/or improve patient compliance.     

Stem Cell-Niche Engineering via Multifunctional Hydrogel Potentiates Stem Cell Therapies for Inflammatory Bone Loss

Effective therapies capable of simultaneously inhibiting inflammation and promoting bone healing remain to be developed for inflammatory bone disease. Stem cell therapies hold great promise for a variety of diseases, but their translation is hampered by low cell survival, rapid clearance, and limited functional integration of transplanted stem cells in target tissues. Herein, a multifunctional hydrogel-based stem cell niche engineering strategy is reported for the treatment of inflammatory bone loss. By rationally integrating different functional modules, an injectable hydrogel-based stem niche is engineered, which possesses temperature-triggered gelling performance, inflammation/oxidative stress-resolving activity, stem-cell binding and survival-enhancing capacity, and osteogenesis-promoting capability. Using ectomesenchymal stem cells (EMSCs), effectiveness of this functionally advanced synthetic stem cell niche is demonstrated in rats with periodontitis, a representative inflammatory bone loss disease. Synergistic effects of the multifunctional hydrogel and EMSCs are also confirmed, with respect to normalizing the pathological microenvironment and improving alveolar bone regeneration in the periodontal tissue. Mechanistically, inflammation/oxidative stress-resolving and osteogenic differentiation promoting capacities of the synthetic stem cell niche are mainly achieved by an incorporated nanotherapy via the GDF15/Atf3/c-Fos axis of the MAPK signaling pathway. Besides periodontitis, the newly engineered hydrogel-stem cell therapies are promising for the treatment of other inflammatory bone defects.