Tranexamic acid-loaded catechol-modified hyaluronic acid/carboxymethyl chitosan double cross-linked porous gel micropowders for rapid hemostasis and wound healing.

Acquiring rapid and effective hemostasis remains a critical clinical challenge. Current researches focus on concentrating blood components to speed up the hemostatic while ignore the effect of anti-fibrinolysis in promoting blood coagulation. Herein, we designed a novel tranexamic acid (TA)-loaded physicochemical double cross-linked multifunctional catechol-modified hyaluronic acid-dopamine/carboxymethyl chitosan porous gel micropowders (TA&Fe3+@HA-DA/CMCS PGMs) for rapid hemostasis and wound healing. TA&Fe3+@HA-DA/CMCS PGMs exhibited high water absorption rate (505.9 ± 62.1 %) and rapid hemostasis (79 ± 4 s) in vivo. Catechol groups, Fe3+ and the protonated amino groups of CMCS induced bacterial death. Moreover, TA&Fe3+@HA-DA/CMCS PGMs displayed sufficient adhesion to a variety of wet rat tissues. TA&Fe3+@HA-DA/CMCS PGMs on various bleeding wounds, including rat liver injury and tail severed models showed excellent hemostasis performance. The TA&Fe3+@HA-DA/CMCS PGMs could promote the healing of full-thickness skin wounds on the backs of rats. The advantages of TA&Fe3+@HA-DA/CMCS PGMs including rapid hemostasis, effective wound healing, good tissue adhesion, antibacterial properties and ease of use make it potentially valuable in clinical application.

Nanofiber Composite Microchannel-Containing Injectable Hydrogels for Cartilage Tissue Regeneration.

Articular cartilage tissue is incapable of self-repair and therapies for cartilage defects are still lacking. Injectable hydrogels have drawn much attention in the field of cartilage regeneration. Herein, the novel design of nanofiber composite microchannel-containing hydrogels inspired by the tunnel-piled structure of subway tunnels is proposed. Based on the aldehydized polyethylene glycol/carboxymethyl chitosan (APA/CMCS) hydrogels, thermosensitive gelatin microrods (GMs) are used as a pore-forming agent, and coaxial electrospinning polylactic acid/gelatin fibers (PGFs) loaded with kartogenin (KGN) are used as a reinforcing agent and a drug delivery system to construct the nanofiber composite microchannel-containing injectable hydrogels (APA/CMCS/KGN@PGF/GM hydrogels). The in situ formation, micromorphology and porosity, swelling and degradation, mechanical properties, self-healing behavior, as well as drug release of the nanofiber composite microchannel-containing hydrogels are investigated. The hydrogel exhibits good self-healing ability, and the introduction of PGF nanofibers can significantly improve the mechanical properties. The drug delivery system can realize sustained release of KGN to match the process of cartilage repair. The microchannel structure effectively promotes bone marrow mesenchymal stem cell (BMSC) proliferation and ingrowth within the hydrogels. In vitro and animal experiments indicate that the APA/CMCS/KGN@PGF/GM hydrogels can enhance the chondrogenesis of BMSCs and promote neocartilage formation in the rabbit cartilage defect model.

Injectable, self-healing poly(amino acid)-hydrogel based on phenylboronate ester bond for osteochondral tissue engineering.

A new generation of osteochondral integrated scaffolds is needed for articular osteochondral regeneration, which can not only facilitate the accurate construction of osteochondral scaffolds in a minimally invasive manner but also firmly combine the subchondral bone layer and cartilage layer. Herein, an osteochondral integrated hydrogel scaffold was constructed by the poly(L-glutamic acid) (PLGA) based self-healing hydrogels with phenylboronate ester (PBE) as the dynamic cross-linking. The bone layer self-healing hydrogel (hydrogel O-S) was prepared by physically blending nanohydroxyapatite into the self-healing hydrogel PLGA-PBE-S, which was fabricated by 3-aminophenylboronic acid/glycidyl methacrylate-modified PLGA (PLGA-GMA-PBA) and 3-amino-1,2-propanediol/N-(2-aminoethyl) acrylamide-modified PLGA (PLGA-ADE-AP). The cartilage layer self-healing hydrogel (hydrogel C-S) was prepared by PLGA-GMA-APBA and glucosamine- modified PLGA-ADE-AP (PLGA-ADE-AP-G). Excellent injectability and self-healing profiles of hydrogel O-S and C-S were observed, the self-healing efficiencies were 97.02% ± 1.06% and 99.06% ± 0.57%, respectively. Based on the injectability and spontaneous healing on the interfaces of hydrogel O-S and C-S, the osteochondral hydrogel (hydrogel OC) was conveniently constructed in a minimally invasive manner. In addition,in situphotocrosslinking was used to enhance the mechanical strength and stability of the osteochondral hydrogel. The osteochondral hydrogels exhibited good biodegradability and biocompatibility. The osteogenic differentiation genes BMP-2, ALPL, BGLAP and COL I of adipose-derived stem cells (ASCs) in the bone layer of the osteochondral hydrogel were significantly expressed, and the chondrogenic differentiation genes SOX9, aggrecan and COL II of ASCs in the cartilage layer of the osteochondral hydrogel were obviously upregulated after 14 d of induction. The osteochondral hydrogels could effectively promote repair of osteochondral defects after 3 months post-surgery.

Building a Poly(amino acid)/Chitosan-Based Self-Healing Hydrogel via Host-Guest Interaction for Cartilage Regeneration.

Cartilage injury is a very common joint disease, and cartilage repair is a great challenge in clinical treatment due to the specific structure of cartilage tissue and its microenvironment in vivo. The injectable self-healing hydrogel is a very promising candidate as a cartilage repair material because of its special network structure, high water retention and self-healing properties. In this work, a self-healing hydrogel cross-linked by host-guest interaction between cyclodextrin and cholic acid was developed. The host material was composed of ß-cyclodextrin and 2-hydroxyethyl methacrylate-modified poly(l-glutamic acid) (P(LGA-co-GM-co-GC)), while the guest material was chitosan modified by cholic acid, glycidyl methacrylate, and (2,3-epoxypropyl)trimethylammonium chloride (EPTAC) (QCSG-CA). The host-guest interaction self-healing hydrogels, named as HG hydrogels (HG gel), exhibited excellent injectability and self-healable property, and the self-healing efficiency was greater than 90%. Furthermore, in order to enhance the mechanical properties and slow down the degradation of the HG gel in vivo, the second network was constructed by photo-cross-linking in situ. Biocompatibility tests showed that the enhanced multi-interaction hydrogel (MI gel) was extremely suitable for cartilage tissue engineering both in vitro and in vivo. In addition, the adipose derived stem cells (ASCs) in MI gel were able to differentiate cartilage effectively in vitro in the presence of inducing agents. Subsequently, the MI gel without ASCs was transplanted into rat cartilage defects in vivo for the regeneration of cartilage. After 3 months postimplantation, new cartilage tissue was successfully regenerated in a rat cartilage defect. All results indicated that the injectable self-healing host-guest hydrogels have important potential applications in cartilage injury repair.

Injectable, In Situ Self-cross-linking, Self-healing Poly(l-glutamic acid)/Polyethylene Glycol Hydrogels for Cartilage Tissue Engineering.

Injectable hydrogels have drawn much attention in the field of tissue engineering because of advantages such as simple operation, strong plasticity, and good biocompatibility and biodegradability. Herein, we propose the novel design of injectable hydrogels via a Schiff base cross-linking reaction between adipic dihydrazide (ADH)-modified poly(l-glutamic acid) (PLGA-ADH) and benzaldehyde-terminated poly(ethylene glycol) (PEG-CHO). The effects of the mass fraction and the molar ratio of -CHO/-NH2 on the gelation time, mechanical properties, equilibrium swelling, and in vitro degradation of the hydrogels were examined. The PLGA/PEG hydrogels cross-linked by dynamic Schiff base linkages exhibited good self-healing ability. Additionally, the PLGA/PEG hydrogels had good biocompatibility with bone marrow-derived mesenchymal stem cells (BMSCs) and could effectively support BMSC proliferation and deposition of glycosaminoglycans and upregulate the expression of cartilage-specific genes. In a rat cartilage defect model, PLGA/PEG hydrogels significantly promoted new cartilage formation. The results suggest the prospect of the PLGA/PEG hydrogels in cartilage tissue engineering.

Injectable macro-porous chitosan/polyethylene glycol-silicotungstic acid double-network hydrogels based on "smashed gels recombination" strategy for cartilage tissue engineering.

The lack of interconnected macro-porous structure of most injectable hydrogels lead to poor cell and tissue infiltration. Herein, we present the fabrication of injectable macro-porous hydrogels based on "smashed gels recombination" strategy. Chitosan/polyethylene glycol-silicotungstic acid (CS/PEG-SiW) double-network hydrogels were prepared via dual dynamic interactions. The bulk CS/PEG-SiW hydrogels were then smashed into micro-hydrogels with average sizes ranging from 47.6 to 63.8 µm by mechanical fragmentation. The CS/PEG-SiW micro-hydrogels could be continuously injected and rapidly recombined into a stable porous hydrogel based on the dual dynamic interactions between micro-hydrogels. The average pore size of the recombined porous CS/PEG-SiW hydrogels ranged from 52 to 184 µm. The storage modulus, compress modulus and maximum compressive strain of the recombined porous CS/PEG-SiW1.0 hydrogels reached about 47.2 %, 28.2 % and 127.6 % of the values for their corresponding bulk hydrogels, respectively. The recombined porous hydrogels were cytocompatible and could effectively support proliferation and chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In a rat cartilage defect model, recombined porous CS/PEG-SiW hydrogels could promote cartilage regeneration. Hematoxylin and eosin (H&E), Safranin-O/Fast green and immunohistochemical staining confirmed the accumulation of glycosaminoglycans (GAG) and type II collagen (Col II) in regenerated cartilage.

Progress in Hydrogels for Skin Wound Repair.

As the first defensive line between the human body and the outside world, the skin is vulnerable to damage from the external environment. Skin wounds can be divided into acute wounds (mechanical injuries, chemical injuries, and surgical wounds, etc.) and chronic wounds (burns, infections, diabetes, etc.). In order to manage skin wound, a variety of wound dressings have been developed, including gauze, films, foams, nanofibers, hydrocolloids, and hydrogels. Recently, hydrogels have received much attention because of their natural extracellular matrix (ECM)-mimik structure, tunable mechanical properties, and facile bioactive substance delivery capability. They show great potential application in skin wound repair. This paper first introduces the anatomy and function of the skin, the process of wound healing and conventional wound dressings, and then introduces the composition and construction methods of hydrogels. Next, this paper introduces the necessary properties of hydrogels in skin wound repair and the latest research progress of hydrogel dressings for skin wound repair. Finally, the future development goals of hydrogel materials in the field of wound healing are proposed.

Preparation of Assemblable Chondral and Subchondral Bone Microtissues for Osteochondral Tissue Engineering.

Microtissues exhibit great advantages in injecting with minimum invasiveness, mimicking natural tissues, and promoting tissue regeneration. However, very few studies have focused on the construction of osteochondral microtissues that could simultaneously support hyaline-like cartilage and bone tissue regeneration. In this study, chondral microtissues that could favor the formation of hyaline-like cartilages and subchondral bone microtissues that could repair subchondral defects to support the neo-generated cartilages were successfully constructed for osteochondral tissue engineering. For chondral repair, the developed chondral microgels with high porosity and hydrophilicity could make cells spherical, favor the formation of cell aggregates, and show an excellent differentiation effect toward hyaline-like cartilage, thus contributing to the production of chondral microtissues. For subchondral bone repair, the fabricated subchondral microgels realize cell adhesion and proliferation and support the osteogenic differentiation of stem cells, thus favoring the formation of subchondral bone microtissues. The injectable chondral and subchondral bone microtissues could be stably assembled by Michael addition reaction between sulfhydryl groups of microtissues and double bonds of hydrophilic macromolecular cross-linker. At 12 weeks postimplantation, osteochondral microtissues could support the reconstruction of osteochondral-like tissues. The present study provides new insight into the microtissues for repair of osteochondral tissues.

Peroxidase-Mimetic Copper-Doped Carbon-Dots for Oxidative Stress-Mediated Broad-Spectrum and Efficient Antibacterial Activity.

Carbon dots (CDs) have recently emerged as antibacterial agents and have attracted considerable attention owing to their fascinating merits of small size, facile fabrication, and surface functionalization. Most of them are involved in external light activation or hybridization with other functional nanomaterials. Herein, we present peroxidase-like Cu-doped CDs (Cu-CDs) for in vitro antibacterial applications. The unique peroxidase-mimicking property of the Cu-CDs was demonstrated by tetramethylbenzidine chromogenic assay, electron paramagnetic resonance spectra, and hydroxy radical probe. Escherichia coli and Staphylococcus aureus were chosen as representative gram-negative/positive models against which Cu-CDs exhibited superior antimicrobial activity even at a dosage down to 5 µg/mL. A possible mechanism of action was that the Cu-CDs triggered a catalytic redox reaction of endogenous H2 O2 and glutathione depletion in the bacteria cells, with subsequent oxidative stress and membrane disruption. This work provides a new strategy for the design of microenvironment-responsive antimicrobial nano-agents.

Mussel-Inspired Bisphosphonated Injectable Nanocomposite Hydrogels with Adhesive, Self-Healing, and Osteogenic Properties for Bone Regeneration.

Injectable hydrogels have received much attention because of the advantages of simulation of the natural extracellular matrix, microinvasive implantation, and filling and repairing of complex shape defects. Yet, for bone repair, the current injectable hydrogels have shown significant limitations such as the lack of tissue adhesion, deficiency of self-healing ability, and absence of osteogenic activity. Herein, a strategy to construct mussel-inspired bisphosphonated injectable nanocomposite hydrogels with adhesive, self-healing, and osteogenic properties is developed. The nano-hydroxyapatite/poly(l-glutamic acid)-dextran (nHA/PLGA-Dex) dually cross-linked (DC) injectable hydrogels are fabricated via Schiff base cross-linking and noncovalent nHA-BP chelation. The chelation between bisphosphonate ligands (alendronate sodium, BP) and nHA favors the uniform dispersion of the latter. Moreover, multiple adhesion ligands based on catechol motifs, BP, and aldehyde groups endow the hydrogels with good tissue adhesion. The hydrogels possess excellent biocompatibility and the introduction of BP and nHA both can effectively promote viability, proliferation, migration, and osteogenesis differentiation of MC3T3-E1 cells. The incorporation of BP groups and HA nanoparticles could also facilitate the angiogenic property of endothelial cells. The nHA/PLGA-Dex DC hydrogels exhibited considerable biocompatibility despite the presence of a certain degree of inflammatory response in the early stage. The successful healing of a rat cranial defect further proves the bone regeneration ability of nHA/PLGA-Dex DC injectable hydrogels. The developed tissue adhesive osteogenic injectable nHA/PLGA-Dex hydrogels show significant potential for bone regeneration application.

A New Framework for Robust Heart Rate Measurement Based on the Head Motion State Estimation.

It is of great significance in managing human health, preventing and curing diseases such as heart disease to measure and monitor the physiological parameters accurately and robustly. However, imaging photoplethysmography (iPPG) can be easily affected by the ambient illumination variations or the subject's motions. In this paper, therefore, a novel framework of heart rate (HR) measurement robust to both illumination and motion artefacts is proposed, which combines the projection-plane-switching-based iPPG method (2PS) with the singular spectrum analysis (SSA). Based on the estimation of the head motion state, one reasonable projection plane is firstly determined, the temporally normalized red-green-blue signals are projected onto the plane and a pulse signal is obtained by alpha-tuning. After that, singular spectrum analysis (SSA) is applied to the obtained pulse signal and the normalized B-channel signal of the facial region of interest (ROI) to remove the artefacts remained in the pulse signal. For the self-collected database and the public PURE database, Bland-Altman plots show that the proposed 2PS-SSA has better agreement than the five compared methods, where the mean biases are 0.59 beat per minute (bpm) and 0.034 bpm, with 95% limits from -2.59 bpm to 3.78 bpm and from -1.97 bpm to 2.04 bpm, respectively.

Research on the combination of color channels in heart rate measurement based on photoplethysmography imaging.

SIGNIFICANCE: The measurement of human vital signs based on photoplethysmography imaging (PPGI) can be severely affected by the interference of various factors in the measurement process; therefore, a lot of complex signal processing techniques are used to remove the influence of the interference. AIM: We comprehensively analyze several methods for color channel combination in the color spaces currently used in PPGI and determine the combination method that can improve the quality of the pulse signal, which results in a modified plane-orthogonal-to-skin based method (POS). APPROACH: Based on the analysis of the previous studies, 13 methods for color channel combination in the different color spaces, which can be seen as having potential abilities in measuring vital signs, were compared by employing the average value of signal-to-noise ratio (SNR) and the box-plot in the public databases UBFC-RPPG and PURE. In addition, the pulse signal was extracted through the dual-color space transformation (sRGB → intensity normalized RGB → YCbCr) and fine-tuning on the CbCr plane. RESULTS: Among the 13 methods for color channel combination, the signal extracted by the Cb+Cr combination in the YCbCr color space includes the most pulse information. Furthermore, the average SNR of the modified POS for all the used databases is improved by 69.3% compared to POS. CONCLUSIONS: The methods using prior knowledge are not only simple to calculate but can significantly increase the SNR, which will provide a great help in the practical use of vital sign measurements based on PPGI.

A bilayered scaffold with segregated hydrophilicity-hydrophobicity enables reconstruction of goat hierarchical temporomandibular joint condyle cartilage.

Temporomandibular joint (TMJ) supports chewing, talking or other daily oral activities. So far, it still remains a great challenge to treat the defected TMJ condyle cartilage through tissue engineering technology. Herein, a bilayered scaffold is designed to fully reconstruct the different cartilage matrices of TMJ condyle under same induction condition. The bilayered scaffold with segregated hydrophobicity-hydrophilicity in top and bottom layer is prepared from a low and high content of polyethylene glycol (PEG) crosslinked poly (L-glutamic acid)-g-polycaprolactone (PLGA-g-PCL). The hydrophobic aggregates in top layer support the adhesion and spread of bone mesenchymal stem cells (BMSCs), thus inducing the differentation towards fibrocartilage; while aggregates (spheroids) are formed on the hydrophlic bottom layer, showing a preferable hyaline differentiation pathway under same chondrogenic induction in vitro. After 14 d in vitro induction, the scaffold/BMSCs construct is implanted in goat TMJ condyle defects. The post-operative outcome after 2 months demonstrates that the defects are fully covered by neo-cartilage. And the regenerated hierarchical TMJ condyle cartilage perfectly consist of ordered fibrocartilage and hyaline cartilage, which is same as natural condyle cartilage. These results corroborate that this bilayered scaffold with segregated hydrophilicity-hydrophobicity carrying induced BMSCs is a promising for treatment of TMJ condyle cartilage defects.

A measurement of illumination variation-resistant noncontact heart rate based on the combination of singular spectrum analysis and sub-band method.

BACKGROUND AND OBJECTIVE: The imaging photoplethysmography method is a non-contact and non-invasive measurement method that usually uses surrounding illumination as an illuminant, which can be easily influenced by the surrounding illumination variations. Thus, it has a practical value to develop an efficient method of heart rate measurement that can remove the interference of illumination variations robustly. METHOD: We propose a novel framework of heart rate measurement that is robust to illumination variations by combining singular spectrum analysis and sub-band method. At first, we extract the blood volume pulse signal by applying the modified sub-band method to the raw facial RGB trace signals. Then the spectra for the interference of illumination variations are extracted from the raw signal obtained from facial regions of interest by using singular spectrum analysis. Finally, we estimate the more robust heart rate through comparison analysis between the spectra of the extracted blood volume pulse signal and the illumination variations. RESULTS: We compared our method with several state-of-the-art methods through the analysis using the self-collected data and the UBFC-RPPG database. Bland-Altman plots and Pearson correlation coefficients pointed out that the proposed method could measure the heart rate more accurately than the state-of-the-art methods. For the self-collected data and the UBFC-RPPG database, Bland-Altman plots showed that proposed method caused better agreement with 95% limits from -4 bpm to 10 bpm and from -2 bpm to 4 bpm respectively than the other state-of-the-art methods. It also revealed that the highly linear relation was held between the estimated heart rate and ground truth with the correlation coefficients of 0.89 and 0.99, respectively. CONCLUSION: By extracting illumination variation directly from the facial region of interest rather than from the background region of interest, the proposed method demonstrates that it can overcome the drawbacks of the previous methods due to the illumination variation difference between the background and facial regions of interest. It can be found that the proposed method has a relatively good robustness regardless of whether illumination variation exists or not.

In Situ Precipitation of Cluster and Acicular Hydroxyapatite onto Porous Poly(γ-benzyl-l-glutamate) Microcarriers for Bone Tissue Engineering.

Bone tissue engineering scaffold based on microcarriers provides an effective approach for the repair of irregular bone defects. The implantation of microcarriers by injection can reduce surgical trauma and fill various irregular shaped bone defects. Microcarriers with porous structure and osteogenic properties have shown great potential in promoting the repair of bone defects. In this study, two kinds of hydroxyapatite/poly-(γ-benzyl-l-glutamate) (HA/PBLG) microcarriers were constructed by emulsion/in situ precipitation method and their structures and properties were studied. First, PBLG porous microcarriers were prepared by an emulsion method. Surface carboxylation of PBLG microcarriers was performed to promote the deposition of HA on PBLG microcarriers. Next, the modified porous PBLG microcarriers were used as the matrix, combined with the in situ precipitation method; the cluster HA and acicular HA were precipitated onto the surface of porous microcarriers in the presence of ammonia water and tri(hydroxymethyl)aminomethane (Tris) solution, respectively. The micromorphology, composition, and element distribution of the two kinds of microcarriers were characterized by TEM, SEM, and AFM. Adipose stem cells (ADSCs) were cultured on the cluster HA/PBLG and acicular HA/PBLG microcarriers, respectively. ADSCs could grow and proliferate normally on both kinds of microcarriers wherein the acicular HA/PBLG microcarriers were more favorable for early cell adhesion and showed a beneficial effect on mineralization and osteogenic differentiation of ADSCs. Successful healing of a rabbit femur defect verified the bone regeneration ability of acicular HA/PBLG microcarriers.

All-in-One Hydrogel Realizing Adipose-Derived Stem Cell Spheroid Production and In Vivo Injection via "Gel-Sol" Transition for Angiogenesis in Hind Limb Ischemia.

Adipose-derived stem cell (ASC) spheroids exhibit enhanced angiogenic efficacy toward ischemia treatment. Thus, it is necessary to develop an all-in-one platform that enables efficient spheroid production, collection, and injectable implantation in vivo. The present study fabricated a poly(l-glutamic acid) (PLGA)-based porous hydrogel that can not only produce ASC spheroids but also conveniently collect spheroids for in vivo implantation via minimally invasive injection to treat hind limb ischemia. PLGA was cross-linked with cystamine (Cys), which contains disulfide bonds, to form a porous hydrogel that could realize "gel-sol" transition by the reduction effect of glutathione (GSH). For one thing, it was found that the introduction of the disulfide bond in the PLGA hydrogel promoted cellular adhesion via combining fibronectin, preventing the formation of spheroids, while the introduction of polyethylene glycol monomethyl ether (mPEG) could disturb the effect of the disulfide bond on cellular adhesion, supporting spheroid formation inside the porous hydrogel. For another, the porous hydrogel transferred into a syringe could turn into liquid polymer solution within about 40 min for collection of the produced spheroids and in vivo injection. In addition, because of the lubrication of polymer solution, the spheroids were protected during the injection of the spheroids/polymer suspensoid through a 25G syringe needle, avoiding damages from shearing. After the in vivo injection, the enhanced paracrine secretion of ASC spheroids resulted in promoted angiogenesis and muscle regeneration, exhibiting obvious therapeutic effect on limb ischemia in mice after 21 days. At the same time, PLGA-based material exhibited well-performed biocompatibility in vivo.

Thermoresponsive Chitosan/DOPA-Based Hydrogel as an Injectable Therapy Approach for Tissue-Adhesion and Hemostasis.

Chitosan (CS) hydrogels are widely used in wound hemostatic agents due to their superior biocompatibility, biodegradability, and hemostatic effect. However, most of them fail to achieve great hemostatic effect because of poor adhesion to bleeding tissues. Also, the conventional implantation surgery of hemostatic hydrogels to internal bleeding wounds may cause secondary trauma to the human body. In this work, catechol-hydroxybutyl chitosan (HBCS-C) has been designed and prepared by grafting hydroxybutyl groups and catechol groups to the CS backbones. The multifunctional HBCS-C hydrogels are fabricated with the properties of thermosensitivity, injectability, tissue-adhesion, biodegradation, biocompatibility, and wound hemostasis. They exhibit excellent liquid-gel transition at different temperatures, through the changes of hydrophilic-hydrophobic interaction and hydrogen bonds generating from hydroxybutyl groups. By the multiple interactions between catechol groups/amino groups and tissues, the biocompatible hydrogels can strongly adhere on the surface of tissue. To further study, the bleeding rat-liver models are made to evaluate the hemostatic effects. After injecting the hydrogel precursor solution into the rat body, the hydrogels are not only formed in situ within 30 s but are also firmly adhered to the bleeding tissues which shows effective hemostasis. The injectability and tissue-adhesion improvement in this study gives a new insight into hemostatic agents, and the multifunctional hydrogels have a great potential in the biomedical application.

Biomimetic Bilayer Scaffold as an Incubator to Induce Sequential Chondrogenesis and Osteogenesis of Adipose Derived Stem Cells for Construction of Osteochondral Tissue.

Toward osteochondral tissue construction, the present study introduced a bilayer scaffold to induce sequential chondrogenesis and osteogenesis of stem cells in vitro. Two scaffolds that are both based on poly(l-glutamic acid) (PLGA) and chitosan (CS) were combined to form the bilayer scaffold. The cartilage region was the covalently cross-linked PLGA/CS hydrogel with a tubular pore structure, possessing a swollen network to prevent cellular adhesion, while inducing spontaneous cellular aggregate formation. The bone region was the electrostatically cross-linked PLGA-grafted nano hydroxyapatite (nHA-g-PLGA)/CS scaffold, which supported cellular adhesion and spreading. Human adipose derived stem cells (hASCs) were seeded into the cartilage region and observed to aggregate, formimg multicellular spheroids, which subsequently fused to rod-like aggregates with a larger size. At the same time, hASCs in aggregates crossed the interface and entered the bone region, presenting adhesion and spreading. With the induction of bone morphogenetic protein 2 (BMP-2) and insulin-like growth factor 1 (IGF-1) during the first 14 days and BMP-2 alone during the last 14 days, hASCs aggregates in the cartilage region underwent chondrogenesis, expressing an abundant cartilage matrix including glycosaminoglycans (GAGs) and type II collagen (COL II) at 28 days. The chondrogenic induced hASCs migrated in the bone region turned to osteogenesis at 28 days, which was associated with their large spreading area and the switch of the induce factor. Thus, the present bilayer scaffold induced the different distribution of hASCs, resulting in subsequent chondrogenesis and osteogenesis, realizing osteochondral tissue construction in vitro.

Biodegradable High-Strength Hydrogels with Injectable Performance Based on Poly(l-Glutamic Acid) and Gellan Gum.

Currently, biodegradable hydrogels are one of the most promising materials in tissue engineering. From the perspective of clinical needs, hydrogels with high strength and minimally invasive implantation are preferred for the reconstruction of load-bearing tissues. In this work, a biodegradable, high-strength, and injectable hydrogel was developed by one-step photo-cross-linking of two biomacromolecules, polyethylene glycol acrylated poly(l-glutamic acid) (PLGA-APEG) and methacrylated gellan gum (GG-MA). The hydrogels, named as PLGA/GG hydrogels, exhibited high mechanical properties. The compression stress of the hydrogels was 0.53 MPa, and the fracture energy was 7.7 ± 0.2 kJ m-2. Meanwhile, the storage modulus could reach 44.0 ± 0.6 kPa. The hydrogel precursor solution loaded with adipose-derived stem cells (ASCs) was subcutaneously injected into C57BL/6 mice and then cross-linked via in situ transdermal irradiation, which demonstrated the excellent injectability and subcutaneous gelatinization of PLGA/GG hydrogels as cell carriers. Furthermore, three-dimensional encapsulation of ASCs in hydrogels after 7, 14, and 21 days showed outstanding cytocompatibility, and the viability of ASCs was up to 84.0 ± 1.7%. The PLGA/GG hydrogels exhibited ideal behaviors of degradation, with 60 ± 5% of hydrogels degraded in phosphate buffered solution (PBS) after 11 weeks. H&E staining demonstrated that the hydrogels degraded gradually after 6 weeks and supported tissue invasion without inflammatory reactions, which indicated the laudable biodegradability of hydrogels. Hence, the biodegradable and high-strength hydrogels with well-performed injectability and biocompatibility possessed high potential applications in tissue engineering, especially in load-bearing tissue regeneration.

Stack-Based Hydrogels with Mechanical Enhancement, High Stability, Self-Healing Property, and Thermoplasticity from Poly(l-glutamic acid) and Ureido-Pyrimidinone.

Supramolecular hydrogels formed by noncovalent bonds are attractive "smart" materials, which can rapidly respond to external stimuli. However, only a handful of supramolecular hydrogels is applicable in tissue engineering, due to the instability and poor mechanical strength of noncovalent cross-linking hydrogels. Thus, a rigid and stable supramolecular hydrogel has been developed based on poly(l-glutamic acid) and 2-ureido-4[1H]pyrimidinones (UPy), and the UPy stacks are noncovalent cross-linking interactions. The hydrogels show excellent mechanical strength and stability, in sharp contrast to noncovalent hydrogels cross-linked by UPy dimers and covalent hydrogels cross-linked by esterification. The hydrogels also exhibit remoldability, self-healing, and thermoplastic printing characteristics, which are caused by the reversible supramolecular property of UPy stacks. Also, the formation of hydrogels dependent on UPy stacks is further investigated by atomic force microscope, small-angle X-ray scattering, in situ X-ray diffraction, circular dichroism, and UV-vis spectroscopies. Finally, the hydrogels show commendable biocompatibility and degradability, which have high potential applications in regenerative medicine.