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The efficacy of chemotherapeutic procedures relies on delivering proper concentrations of anti-cancer drugs in the tumor surroundings, so as to prevent potential side effects on healthy tissues. Novel drug carrier platforms should not just be able to deliver anticancer molecules, but also allow for adjustements in the way these drugs are administered to the patients. We developed a system for delivering water-insoluble drugs, based on the use of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or bis(2-ethylhexyl) sulfosuccinate benzyl-n-hexadecyldimethylammonium (BHD-AOT), embedded into oxidized alginate-gelatin (ADA/Gel) hydrogel, emulating a patch for topic applications. After being loaded with curcumin, cancer cells such as human colorectal adenocarcinoma (HCT116 and DLD-1) and melanoma cell lines (MEL501), and non-malignant cells such as mammary epithelial cell lines (NMuMG) and embryonal fibroblasts (NIH 3T3 or NEO cells) were analyzed for biocompatibility and cytotoxic effects. The results show that the proposed system can load comparatively higher concentrations of the drug (with respect to other nano/microcarriers in the literature), and that it can enhance the likelihood of the drug being uptaken by cancer cells instead of non-malignant cells. These assays were complemented by diffusion studies across the stratum corneum of rat skin, with the aim of determining the system's efficiency during topical application. Finally, the stability of the patch was tested after lyophilization to determine its potential pharmaceutical use. As a whole, the combined system represents a highly reliable and robust method for embedding and delivering complex insoluble chemotherapeutical molecules, and it is less invasive than other alternative methods in the literature.

Elevated brain choline is associated with better executive functions in preadolescents. Manipulating dietary choline prospectively in preadolescents using egg supplementation could improve executive functions via effects on brain cellular and neurotransmitter functions.We tested the 9-month impacts of egg supplementation on executive functions. It was hypothesized that preadolescents who consumed meal or snack replacement products containing powder made from whole eggs would have the largest improvements in executive functions after 9 months compared to those consuming similar products with either added milk powder or gelatin as a placebo.A randomized, parallel-group, double-blinded, placebo-controlled trial design was used. The executive functions of 122 preadolescents (58 females) aged 9-13 were analyzed before and after the 9-month intervention. The primary outcomes were 3 NIH Toolbox-Cognitive Battery measures of executive function: mental flexibility, working memory, and selective attention and inhibitory control. Participants were randomized to consume food products with either: 1) whole egg powder; 2) milk powder; or 3) gelatin as a placebo, all matched on macronutrient content and used as replacements for commonly consumed foods (i.e., waffles, pancakes, macaroni and cheese, ice cream, and brownies). Hypothesis testing used mixed-effects models that included physical activity and sleep scores as covariates.A statistically significant group × time interaction for selective attention and inhibitory control was found (P = 0.049) for the milk group. This interaction resulted from no change for the placebo group and an improvement in selective attention and inhibitory control performance for the milk group by a T-score of 5.8; the effect size (d) was 0.44 SD units. Other comparisons were statistically insignificant.Consumption of foods with added milk powder as a replacement for snacks or meals for 9 months improves selective attention and inhibitory control in preadolescents. Replacement of foods with added whole egg powder does not impact 9-month changes in preadolescent executive functions. This trial was registered at clinicaltrials.gov as NCT03739424.

Japan is one of the countries conducting longitudinal serosurveillance of vaccine-preventable diseases. We conducted surveillance of the local measles-specific antibody titer, calculated the effective reproduction number (R

In this work, a positively charged chitosan-grafted-polyarginine (CS-N-PArg) as the macro-molecular NO donor, and a negatively charged acetalated starch (AcSt-O-PAsp) as a glucose donor, have been synthesized. To achieve the multi-enzymatic cascade system for local generation of self-supply glucose to increase the H

The conjunctiva covers the largest area of ocular surface and is responsible for tear balance and clear vision. After trauma or surgery, the conjunctiva is prone to scarring and contracture. Transplantation with suture often implies numerous complications, such as inflammation, suture erosion, granuloma. And the suture needs to be removed, which means a secondary trauma. In this study, a bioadhesive hydrogel (GMO) for sutureless conjunctival transplantation was developed based on a semi-interpenetrating polymer network (sIPN) consisting of gelatin methacrylate (GelMA) and oxidized hyaluronic acid (OHA). The maximum adhesion strength was 157 ± 17 kPa, and the burst pressure was 357 ± 29 kPa, which was 15 times higher than the human intraocular pressure (IOP). GMO bioadhesive hydrogel significantly improved surgical efficiency and secured the collagen scaffold firmly to a rabbit conjunctival defect. The sutureless transplantation approach revealed the promoted tissue repair without scar. In conclusion, GMO bioadhesive may be an attractive alternative to suture for ocular surface reconstruction by avoiding suture-related complications and improving clinical outcome. STATEMENT OF SIGNIFICANCE: Conjunctival tissue is prone to scarring and contracture after trauma, and surgery with sutures often implies numerous complications. In this study, the ocular surface reconstruction was achieved by sutureless transplantation of conjunctival scaffold using bioadhesive hydrogel. The prepared GMO bioadhesive based on the semi-interpenetrating network of gelatin methacrylate (GelMA) and oxidized hyaluronic acid (OHA) had favorable adhesion and mechanical properties. The sutureless transplantation approach significantly improved the operation efficiency, avoided suture-related complications, and promoted the regeneration of conjunctiva. This study highlights the great potential of the sutureless repair strategy for clinical application in ocular surface reconstruction.

Conductive hydrogel-based flexible electronics have attracted immense interest in wearable sensor, soft robot and human-machine interface. However, the application of hydrogels in flexible electronics is limited by the deterioration of mechanical and electrical properties due to freezing at low temperature and desiccation after long-term use. Meanwhile, flexible electronics based on hydrogel are usually not breathable, which has a great impact on wearing comfort and signal stability in long-term sensing. In this work, an adjustable porous gelatin/polypyrrole/reduction graphene oxide (Gel/PPy/rGO) organohydrogel with high breathability (14 g∙cm

In the present study, biocompatible nanofibers containing aqueous extracts from Muscari neglectum (M. neglectum) plants (produced nanofiber) were prepared and their antifungal and cytotoxicity effects were investigated. For this purpose, the extracts obtained from flowers, stem leaves, and fresh onion from M. neglectum were lyophilized at various concentrations. Produced nanofibers were prepared using electrospinning techniques. During the electrospinning process, two auxiliary natural polymers including gelatin and chitosan were used. After synthesis, the physicochemical properties of the nanofibers were confirmed by Scanning Electron Microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray energy diffraction spectroscopy (EDS or EDX), and Differential Scanning Calorimetry (DSC). The electrospun produced nanofibers have continuous and uniform structures. The cytotoxicity assay of these electrospun nanofibers were done on Human dermal fibroblast cell (HDF) and HUVEC cell (Human Umbilical Endothelial Cells) lines and results showed that nanofiber doesn't have any toxicity to normal cell lines. For anti-fungal activity tests, the appropriate amounts of nanofibers containing M. neglectum were placed in media with five different fungal species utilizing two methods: disc diffusion and well diffusion. In vitro results showed that all electrospun nanofibers containing M. neglectum had strong antifungal activity against Candida albicans, Glabrata, Parapacillus, Guillermoides, Crocus fungi species. Our findings also showed that nanofibers containing 86.88% polyvinyl alcohol/ gelatin/ chitosan/ M. neglectum root extract (produced nanofibers) were had better swelling and physicochemical properties and stronger antifungal activity than others (fiber formed with plant root). In a nutshell, natural nanofibers can be used as a beneficial drug delivery system.

Gelatin methacrylate (GelMA) and hyaluronic acid methacrylate (HAMA) are frequently used biomaterials for 3D bioprinting, with individual well-established material characteristics. To identify an ideal combination of GelMA and HAMA for chondrogenesis, a novel, primary human chondrocyte COL2A1-Gaussia luciferase reporter system (HuCol2gLuc) was developed. With this non-destructive, high-throughput temporal assay, Gaussia luciferase is secreted from the cells and used as a proxy for measuring type II collagen production. GelMA:HAMA ratios were screened using the reporter system before proceeding to 3D bioprinting. This method is efficient, saving on time and materials, resulting in a streamlined process of biomaterial optimization. The screen revealed that the addition of HAMA to GelMA improved chondrogenesis over GelMA (15%) alone. Storage moduli were measured using dynamic mechanical analysis of the same GelMA:HAMA ratios and established an initial threshold for chondrogenesis of ∼30kPa. To determine if biomaterial storage moduli impact cell mobility, human primary chondrocytes transduced with green fluorescent protein (GFP) were 3D bioprinted in either 1:1 or 2:1 ratios with storage moduli of 32kPa and 57.9kPa, respectively. We found that reduced cell mobility, in the stiffer biomaterial, had higher type II collagen expression, than the softer material with more cell mobility. Finally, after 3D bioprinting with HuCol2gLuc cells we successfully identified an optimal combination (2:1) of GelMA:HAMA and photo-crosslinking time (38s) for chondrogenesis. STATEMENT OF SIGNIFICANCE: One challenge of 3D bioprinting is identifying ideal biomaterials that stimulate articular cartilage development. To identify an optimal combination of gelatin methacrylate and hyaluronic acid methacrylate for chondrogenesis we developed a primary human chondrocyte type II collagen Gaussia luciferase reporter cell (HuCol2gLuc). This non-destructive, high-throughput assay uses a secreted Gaussia luciferase as a proxy for temporal type II collagen production. This reporter system streamlines the biomaterial optimization process before 3D bioprinting. We also used it to determine the level of stiffness required for chondrogenesis. And for the first time, we quantified chondrocyte mobility in a 3D bioprinted construct. Together these results indicate that a biomaterial with a higher storage modulus and less cell mobility, improves chondrogenesis.

The endometrium undergoes profound changes in tissue architecture and composition, both during the menstrual cycle as well as in the context of pregnancy. Dynamic remodeling processes of the endometrial extracellular matrix (ECM) are a major element of endometrial homeostasis, including changes across the menstrual cycle. A critical element of this tissue microenvironment is the endometrial basement membrane, a specialized layer of proteins that separates the endometrial epithelium from the underlying endometrial ECM. Bioengineering models of the endometrial microenvironment that present an appropriate endometrial ECM and basement membrane may provide an improved environment to study endometrial epithelial cell (EEC) function. Here, we exploit a tiered approach using two-dimensional high-throughput microarrays and three-dimensional gelatin hydrogels to define patterns of EEC attachment and cytokeratin 18 (CK18) expression in response to combinations of endometrial basement membrane proteins. We identify combinations (collagen IV + tenascin C; collagen I + collagen III; hyaluronic acid + tenascin C; collagen V; collagen V + hyaluronic acid; collagen III; and collagen I) that facilitate increased EEC attachment, increased CK18 intensity, or both. We also identify significant EEC mediated remodeling of the methacrylamide-functionalized gelatin matrix environment via analysis of nascent protein deposition. Together, we report efforts to tailor the localization of basement membrane-associated proteins and proteoglycans in order to investigate tissue-engineered models of the endometrial microenvironment.

Ingestible electronics monitor biometric information from outside the body. Making them with harmless or digestible materials will contribute to further reducing the burden on the patient's oral intake. Here, considering that the inductive part plays an important role in communications, we demonstrate a degradable inductor fabricated with harmless substances. Such a transient component must meet conflicting requirements for both operation and disassembly. Therefore, we integrated a substrate made of gelatin, a thermally degradable material, and a precision coil pattern made of edible gold or silver leaf. However, gelatin itself lost its initial shape easily due to quick sol-gel changes in physiological conditions. Thus, we managed the gelatin's thermal responsiveness by using a tangle of gelatin/chitosan gel networks and genipin, an organic cross-linking agent, and gained insights into the criteria for developing transient devices with thermo-degradability. In addition, to compensate for the lack of water resistance and low conductivity of thin metal foils, we propose a laminated structure with oleogel (beeswax/olive oil). LCR resonance circuits, by connecting a commercial capacitor to the coil, worked wirelessly in the megahertz band and gradually degraded in a warm-water environment. The presented organic electronics will contribute to the future development of transient wireless communications for implantable and ingestible medical devices or environmental sensors with natural and harmless ingredients.

Chemically defined hydrogels are increasingly utilized to define the effects of extracellular matrix (ECM) components on cellular fate determination of human embryonic and induced pluripotent stem cell (hESC and hiPSCs). In particular, hydrogels cross-linked by orthogonal click chemistry, including thiol-norbornene photopolymerization and inverse electron demand Diels-Alder (iEDDA) reactions, are explored for 3D culture of hESC/hiPSCs owing to the specificity, efficiency, cytocompatibility, and modularity of the cross-linking reactions. In this work, we exploited the modularity of thiol-norbornene photopolymerization to create a biomimetic hydrogel platform for 3D culture and differentiation of hiPSCs. A cell-adhesive, protease-labile, and cross-linkable gelatin derivative, gelatin-norbornene (GelNB), was used as the backbone polymer for constructing hiPSC-laden biomimetic hydrogels. GelNB was further heparinized via the iEDDA click reaction using tetrazine-modified heparin (HepTz), creating GelNB-Hep. GelNB or GelNB-Hep was modularly cross-linked with either inert macromer poly(ethylene glycol)-tetra-thiol (PEG4SH) or another bioactive macromer-thiolated hyaluronic acid (THA). The formulations of these hydrogels were modularly tuned to afford biomimetic matrices with similar elastic moduli but varying bioactive components, enabling the understanding of each bioactive component on supporting hiPSC growth and ectodermal, mesodermal, and endodermal fate commitment under identical soluble differentiation cues.

Human umbilical cord mesenchymal stem cells (HUMSCs) are one of the most attractive sources of stem cells, and it is meaningful to design and develop a type of microcarriers with suitable mechanical strength for HUMSCs proliferation in order to acquire enough cells for cell-based therapy. Alginate-gelatin core-shell (AG) soft microcarriers were thus fabricated via a microfluidic device with droplet shearing/gelation facilities and surface coating for in vitro expansion of HUMSCs. The attachment and proliferation of HUMSCs on AG microcarriers with different mechanical strengths modulated by gelatin coating was studied, and the harvested cells were characterized to verity their differentiation potential. The obtained core-shell microcarriers were all uniform in size with a high mono-dispersity (CV 5 %). An increase in the gelatin surface coating concentration from 0.5 % to 1.5 % would lead to the reduction in both the particle size of the microcarriers and swelling ratio upon the contact of culture medium, but increased elastic modulus. Microcarriers of 245.12 μm with a gelatin coating elastic modulus of 27.5 kPa (AG10) were found to be the optimal substrate for HUMSCs with an initial attachment efficiency of 44.41 % and a 5-day expansion efficiency of 647 %. The cells harvested from AG10 still reserved their outstanding pluripotency. Fresh AG10 could smoothly transfer cells from a running microcarrier-cell system of confluence to serve as a convenient way of scaling-up the existing culture. The current study thus developed suitable microcarriers, AG10, for in vitro HUMSCs expansion with well reserve of cell multipotency, and also provided a manufacturing and surface manipulating strategy of precise production and fine regulation of microcarrier properties.

Infection-induced chronic wounds cause prolonged pains, a high risk of amputation, and even increased mortality in immunocompromised patients. Here we report an antibacterial microneedle (MN) patch, which features high degradability in biological fluids and gelatinase-responsive release of an antibacterial photothermal peptide AMP-Cypate. We first synthesize gelatin nanoparticles (GNPs) and then conjugate the AMP-Cypate to afford composite AMP-Cypate@GNPs. The proteinaceous nanoparticles can responsively release AMP-Cypate in the presence of gelatinase, an enzyme secreted specifically by Staphylococcus aureus (S. aureus). AMP-Cypate@GNPs were then deposited in the tips of MNs fabricated by PVP and recombinant human type III collagen (Col III) to devise the antibacterial MN/AMP-Cypate@GNP patches. When applied to the infection site, MNs break through the epidermis and the stratum corneum, dissolve in the infected dermis, reach the bacterial colony or biofilm, release AMP-Cypate@GNPs, and exert a gelatinase-responsive photothermal therapy under near-infrared (NIR) irradiation to kill the pathogen S. aureus. In a rat model of staphylococcal infection-induced chronic wounds mimicking the condition of diabetic foot ulcer, the antibacterial MN/AMP-Cypate@GNP patches eradiated the bacterial infection and resulted in complete healing of the wounds, proving its potential application in the treatment of chronic wound infections and diabetic foot ulcers.

Timely restoration of blood supply following ischemia is critical to rescue damaged tissue. However, clinical efficacy is hampered by the inflammatory response after ischemia. Whether inflammation fine tunes the angiogenesis and the function of blood vessels via the heterogeneity of neutrophils remain poorly understood. Herein, the objective of this work is to incorporate the growth factors secreted by neutrophils into a porous gelatin methacrylate (GelMA) hydrogel, which subsequently is used as a novel regenerative scaffold with defined architecture for ischemia. We demonstrate that anti-inflammatory neutrophils (N

The periosteum plays an important role in the regeneration of critical-size bone defects, with functions of recruiting multiple cells, accelerating vascular network reconstruction, and guiding bone tissue regeneration. However, these functions cannot be easily implemented by simply simulating the periosteum via a material structure design or by loading exogenous cytokines. Herein, inspired by the periosteal function, we propose a biomimetic periosteum preparation strategy to enhance natural polymer hydrogel membranes using inorganic bioactive materials. The biomimetic periosteum having bone tissue self-adhesive functions and resembling an extracellular matrix was prepared using dopamine-modified gelatin and oxidized hyaluronan (GA/HA), and micro/nanobioactive glass (MNBG) was further incorporated into the hydrogel to fabricate an organic/inorganic co-crosslinked hydrogel membrane (GA/HA-BG). The addition of MNBG enhanced the stability of the natural polymer hydrogel membrane, resulting in a sustained degradation time, biomineralization, and long-term release of ions. The Ca

Injuries of the bone-to-tendon interface, such as rotator cuff and anterior cruciate ligament tears, are prevalent musculoskeletal injuries, yet effective methods for repair remain elusive. Tissue engineering approaches that use cells and biomaterials offer a promising potential solution for engineering the bone-tendon interface, but previous strategies require seeding multiple cell types and use of multiphasic scaffolds to achieve zonal-specific tissue phenotype. Furthermore, mimicking the aligned tissue morphology present in native bone-tendon interface in three-dimensional (3D) remains challenging. To facilitate clinical translation, engineering bone-tendon interface using a single cell source and one continuous scaffold with alignment cues would be more attractive but has not been achieved before. To address these unmet needs, in this study, we develop an aligned gelatin microribbon (μRB) hydrogel scaffold with hydroxyapatite nanoparticle (HA-np) gradient for guiding zonal-specific differentiation of human mesenchymal stem cell (hMSC) to mimic the bone-tendon interface. We demonstrate that aligned μRBs led to cell alignment in 3D, and HA gradient induced zonal-specific differentiation of mesenchymal stem cells that resemble the transition at the bone-tendon interface. Short chondrogenic priming before exposure to osteogenic factors further enhanced the mimicry of bone-cartilage-tendon transition with significantly improved tensile moduli of the resulting tissues. In summary, aligned gelatin μRBs with HA gradient coupled with optimized soluble factors may offer a promising strategy for engineering bone-tendon interface using a single cell source. Impact statement Our 3D macroporous microribbon hydrogel platform with alignment cues zonally integrated with hydroxyapatite nanoparticles enables differentiation across the bone-tendon interface within a continuous scaffold. While most interfacial scaffolds heretofore rely on composites and multilayer approaches, we present a continuous scaffold utilizing a single cell source. The synergy of niche cues with human mesenchymal stem cell (hMSC) culture leads to an over 45-fold enhancement in tensile modulus in culture. We further demonstrate that priming hMSCs towards the chondrogenic lineage can enhance the differential osteogenesis. Relying on a single cell source could enhance zone integration and scaffold integrity, along with practical benefits.

There are complications in applying regenerative strategies at the interface of hard and soft tissues due to the limited designs of constructs that can accommodate different cell types in different sites. The problem originates from the challenges in the adhesion of dissimilar materials, such as polymers and hydrogels, that can be suitable for regenerating different tissues such as bone and soft tissues. This paper presents a design of a new hybrid construct in which a polymer (polycaprolactone (PCL)) membrane firmly adheres to a layer of hydrogen (gelatin).PCL membranes with defined size and porosity were fabricated using 3D printing. The gelatin layer was attached to the PCL membranes using the aminolysis procedure. We have examined this construct for the application of Guided Bone Regeneration (GBR) as a typical surgical regenerative procedure of the oral cavity at the interface of bone and soft tissue. Complete in vitro and in vivo investigations on canine tibia bone defects have been performed. Histological analyses for fibrosis morphometric and bone morphometric evaluation, as well as bone-fibrosis histological grading and CBCT imaging, were conducted.Chemical and morphological studies of the membrane proved that gelatin was uniformly attached to the aminolyzed PCL membranes. The in vitro and in vivo studies indicated the membrane's biocompatibility, mechanical stability, and barrier function for the GBR application. Furthermore, in vitro study showed that the membranes could improve osteogenesis and the regeneration of bone defects. The results illustrated that the mean bone density in the membrane groups was about three times more than that of the control group.The fabricated 3D-printed hybrid Gelatin/PCL bi-layered membrane can be a good candidate for interfacial tissue engineering and a promising membrane for GBR procedure.

Leakage is a common complication of surgeries and injuries, causing pain and increasing the economic burden on patients. Although there are commercially available sealants for leakage prevention, few of them are entirely satisfactory due to disease transmission, high cost, and poor biocompatibility. In addition, none of them can be controllably removed for further healthcare. In this paper, by using cohesion design, a sealant based on amino-modified gelatin (AG) and bi-polyethylene glycol

Synthetic scaffolds are needed for generating organized neo-myocardium constructs to promote functional tissue repair. This study investigated the biocompatibility of an elastomeric electrospun degradable polar/hydrophobic/ionic polyurethane (D-PHI) composite scaffold with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The composite material was electrospun to generate scaffolds, with nanofibres oriented in aligned or random directions. These features enabled the authors to evaluate the effect of characteristic elements which mimic that of the native extracellular matrix (alignment, chemical heterogeneity, and fiber topography) on hiPSC-CMs activity. The functional nature of the hiPSC-CM cultured on gelatin and Matrigel-coated scaffolds were assessed, investigating the influence of protein interactions with the synthetic substrate on subsequent cell phenotype. After 7 days of culture, high hiPSC-CM viability was observed on the scaffolds. The cells on the aligned scaffold were elongated and demonstrated aligned sarcomeres that oriented parallel to the direction of the fibers, while the cells on random scaffolds and a tissue culture polystyrene (TCPS) control did not exhibit such an organized morphology. The hiPSC-CMs cultured on the scaffolds and TCPS expressed similar levels of cardiac troponin-T, but there was a higher expression of ventricular myosin light chain-2 on the D-PHI composite scaffolds versus TCPS, indicating a higher proportion of hiPSC-CM exhibiting a ventricular cardiomyocyte like phenotype. Within 7 days, the hiPSC-CMs on aligned scaffolds and TCPS beat synchronously and had similar conductive velocities. These preliminary results show that aligned D-PHI elastomeric scaffolds allow hiPSC-CMs to demonstrate important cardiomyocytes characteristics, critical to enabling their future potential use for cardiac tissue regeneration.

Articular cartilage defects have limited healing potential and, when left untreated, can lead to osteoarthritis. Tissue engineering focuses on regenerating the damaged joint surface, preferably in an early stage. Here, we investigate the regenerative potential of three-dimensional (3D) constructs consisting of human induced pluripotent stem cell (iPSC)-derived chondrocytes in gelatin methacryloyl (GelMA) hydrogel for stable hyaline cartilage production. iPSC-derived chondrocytes are encapsulated in GelMA hydrogel at low (1 × 107 ml-1 ) and high (2 × 107 ml-1 ) density. In a conventional medium, GelMA hydrogel supports the chondrocyte phenotype, as opposed to cells cultured in 3D in absence of hydrogel. Moreover, encapsulated iPSC-derived chondrocytes preserve their in vivo matrix formation capacity after 21 days in vitro. In differentiation medium, hyaline cartilage-like tissue forms after 21 days, demonstrated by highly sulfated glycosaminoglycans and collagen type II. Matrix deposition is delayed at low encapsulation density, corroborating with lower transcript levels of COL2A1. An ectopic assay in nude mice demonstrates further maturation of the matrix deposited in vitro. Direct ectopic implantation of iPSC-derived chondrocyte-laden GelMA, without in vitro priming, also generates hyaline cartilage-like tissue, albeit less mature. Since it is unclear what maturity upon implantation is desired for joint surface regeneration, this is an attractive technology to generate immature and more mature hyaline cartilage-like tissue. ispartof: BIOTECHNOLOGY AND BIOENGINEERING vol:119 issue:10 pages:2950-2963 ispartof: location:United States status: published

Hydrogels are ideal materials for mimicking and engineering soft tissue. Hyaluronic acid is a linear polysaccharide native to the human extracellular matrix. In this study, we first develop and characterize two hydrogel compositions built from oxidized HA and gelatin with and without alginate-di-aldehyde (ADA) crosslinked by ionic and enzymatic agents with potential applications in soft tissue engineering and tissue mimicking structures. The stability under incubation conditions was improved by adjusting crosslinking times. Through large-strain mechanical measurements, the hydrogels' properties were compared to human brain tissue and the samples containing ADA revealed similar mechanical properties to the native tissue specimens in cyclic compression-tension.

Terminal performance of a bullet in human body is critical for the treatment of gunshot injury and optimization of bullet design. The effects of the impact velocity (vBallistic gelatin was used to simulate human body. The 7.62 mm × 39 mm rifle bullets with different vAccording to the distribution of the damaged gelatin along the penetration depth, the damaged gelatin block could be divided into two parts: the less damaged part and the severely damaged part. The length of the less damaged part depends mostly on δThe expansion method is suitable to investigate the influence of different factors of bullets on their terminal performance. The characteristics of the damaged gelatin have a linear relationship with the initial attack angle (δ

With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles.Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (SpongelIn total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOneLiver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.

Micro-/macroangiopathy, neuropathy and prolonged inflammation are common in diabetic wound, however, traditional wound dressing cannot treat these problems in the same time. Herein, we developed a multifunctional hydrogel with promoted angiogenesis, cell proliferation and anti-inflammation ability to treat diabetic wound. The hydrogel was composed of natural polymers, including gelatin and chitosan, which have excellent biocompatibility. Histatin-1 (His-1) was added into the hydrogel to improve the cell adhesion, proliferation and angiogenesis. Besides, polypyrrole based conductive nanoparticles (G-Ppy) were introduced in the hydrogel to enhance the electrical signal conduction between skin and promote the mechanical strength of the hydrogel. The polypyrrole nanoparticles were growth in the chain of methacryloyl grafted gelatin (Gel-MA), leading to a better biocompatibility and water dispersibility. In vivo wound healing experiment proved that the hydrogel accelerated the wound healing rate, down regulation the expression of pro-inflammation factor TNF-α and upregulation the expression of CD31 and α-SMA, indicating the prospects in the application of diabetic wound healing.

Preoperative embolization for intracranial meningiomas can cause tumor necrosis, reduce intraoperative blood loss, and facilitate surgery. This study aimed to evaluate the efficacy of tumor embolization using Embosphere microspheres for skull base meningiomas and analyze postembolization plain computed tomography (CT) and magnetic resonance imaging (MRI) scans to identify findings that could potentially predict treatment response.Between April 2014 and April 2020, 80 patients with skull base meningiomas presenting at our medical center underwent embolization with Embosphere microspheres. The effects of tumor embolization were evaluated through a comparison of postembolization plain CT and contrast-enhanced MRI.A total of 143 vessels (102 of 108 external carotid artery branches and 41 of 65 internal carotid artery branches) from 80 skull base meningiomas were embolized with Embosphere microspheres. Microspheres 100-300 μm in size were used in 2 cases, microspheres 300-500 μm in size were used in 12 cases, and microspheres 500-700 μm in size were used in 66 cases. Postembolization contrast-enhanced MRI showed reductions in enhancing lesions within the tumor in 55 of 80 cases. Postembolization plain CT scans showed high-density lesions within the tumor in 41 of 55 cases. Thus, reductions in enhancing lesions on postembolization contrast-enhanced MRI were statistically significantly associated with the presence of high-density lesions on postembolization plain CT (P0.001). Embolization-related neurological complications occurred in 3 cases.Embosphere microspheres are user friendly and effective embolic materials for the embolization of skull base meningiomas. Postembolization contrast-enhanced MRI and plain CT findings may be useful for evaluating the effects of tumor embolization.

Burn injury remains a serious cause of morbidity and mortality worldwide. Severity of burns is determined by the percentage of burned area compared to the body surface area, age of patient, and by the depth of skin and soft tissue involvement; these factors determine management as well as prospective outcomes. The pathophysiology of partial- to full-thickness burn conversion remains poorly understood and is associated with a worse overall prognosis. Recent studies have demonstrated that an altered inflammatory response may play a significant role in this conversion and therefore a reduction in early inflammation is crucial to ultimately decreasing burn severity and morbidity. We hypothesize that the application of a microcapillary gelatin-alginate hydrogel loaded with anti-TNF-α (infliximab) monoclonal antibodies to a partial-thickness burn will reduce inflammation within partially burned skin and prevent further progression to a full-thickness burn.Assembly of the microfluidic hydrogels is achieved by embedding microfibers within a hydrogel scaffold composed of a gelatin-alginate blend, which is then soaked in a solution containing anti-TNF-α antibodies for drug loading. 12 young (2-4 months) and 12 old (16 months) mice were given partial thickness burns. The treatment cohort received the anti-TNF-α infused hydrogel with an occlusive dressing and the control cohort only received an occlusive dressing. Mice were euthanized at post-burn day 3 and skin samples were taken. Burn depth was evaluated using Vimentin immunostaining.All mice in the treatment cohort demonstrated decreased conversion of burn from partial to full thickness injury (old = p0.01, young = p0.001) as compared to the control group. Old mice had greater depth of burn than young mice (p0.001). There were greater eosinophils in the treatment cohort for both young and old mice, but it did not reach statistical significance.The application of a novel microcapillary gelatin-alginate hydrogel infused with anti-TNF-α antibody to partial thickness burns in mice showed reduction in partial to full thickness burn secondary progression as compared to controls using this murine model; this promising finding might help decrease the high morbidity and mortality associated with burn injuries.

Intravenous fluids for perioperative infusion therapy should be isotonic to maintain the body fluid homeostasis in children. Modified fluid gelatin 4% in a balanced electrolyte solution has a theoretical osmolarity of 284 mosmol LWe thus hypothesized that the infusion of gelatin would be expected to decrease plasma osmolality. We performed an in-vitro experiment and an in-vivo study to evaluate the impact of gelatin on the osmolality in children.In the in-vitro experiment, full blood samples were diluted with gelatin 4% or albumin (50 g LIn the in-vitro experiment, 65 gradually diluted blood samples from five volunteers (age 25-55 years) were analyzed. The dilution with gelatin caused no significant changes in osmolality between 0% and 100%. Compared with gelatin, the osmolality in the albumin group was significantly lower between 50% and 100% dilution (p .05). In the in-vivo study, 221 children (age 21.4 ± 30 months) were included. After gelatin infusion, the osmolality increased significantly (mean change 4.3 ± 4.8 [95% CI 3.7-4.9] mosmol kg HGelatin in a balanced electrolyte solution has isotonic characteristics in-vitro and in-vivo, despite the low theoretical osmolarity, probably caused by the (unmeasured) negative charges in the gelatin molecules contributing to the plasma osmolality. For a better evaluation of the (real) tonicity of gelatin-containing solutions, we suggest to calculate the osmolality (mosmol kg HClinicalTrials.gov (ID: NCT02495285).

The purpose of this article was to describe the successful diagnosis and management of clinically atypical, unilateral, gelatinous drop-like corneal dystrophy (GDLD) in a pediatric patient.This study was a case report.A 7-year-old Japanese girl was referred to our clinic with right corneal opacity for over 3 years. Slitlamp examination revealed a white, protruding, paracentral corneal opacity with an irregular surface and tiny stromal lattice figures with subepithelial opacities. No trichiasis or epiblepharon was observed, and the patient's right corrected distance visual acuity (CDVA) was 18/20. The contralateral cornea was intact but demonstrated fluorescein uptake. After 8 months, the right CDVA worsened from 18/20 to 6/20, and corneal epithelial scraping was performed. Histopathological analysis revealed amyloid nodules in the subepithelial layer and in the anterior corneal stroma stained with Congo red, which reoccurred 2 months after the procedure, and corneal dystrophy was suspected. Isolation and sequencing of the genomic DNA revealed a homozygous p.Gln118Ter. mutation in TACSTD2 in the patient and heterozygous p.Gln118Ter. mutations in both parents. GDLD was diagnosed; bilateral use of therapeutic soft contact lenses was prescribed after the first corneal scraping. No additional surgical intervention was required for the right eye for 4.5 years. CDVA of the contralateral left eye has been successfully maintained at 30/20 over this period, without emergence of nodular lesions or corneal opacities.We encountered a patient with early, atypical GDLD, who was definitively diagnosed using genomic DNA sequencing. GDLD should be a part of the differential diagnosis in patients presenting with unilateral, recurrent amyloid deposition.

The objective of this research is to develop an imaging method with cationized gelatin nanospheres incorporating molecular beacon (cGNS

In this study, we developed three-dimensional (3D) printed annular ring-like scaffolds of hydrogel (gelatin–alginate) constructs encapsulated with a mixture of human cardiac AC16 cardiomyocytes (CMs), fibroblasts (CFs), and microvascular endothelial cells (ECs) as cardiac organoid models in preparation for investigating the role of microgravity in cardiovascular disease initiation and development. We studied the mechanical properties of the acellular scaffolds and confirmed their cell compatibility as well as heterocellular coupling for cardiac tissue engineering. Rheological analysis performed on the acellular scaffolds showed the scaffolds to be elastogenic with elastic modulus within the range of a native in vivo heart tissue. The microstructural and physicochemical properties of the scaffolds analyzed through scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy-attenuated total reflectance (ATR-FTIR) confirmed the mechanical and functional stability of the scaffolds for long-term use in in vitro cell culture studies. HL-1 cardiomyocytes bioprinted in these hydrogel scaffolds exhibited contractile functions over a sustained period of culture. Cell mixtures containing CMs, CFs, and ECs encapsulated within the 3D printed hydrogel scaffolds exhibited a significant increase in viability and proliferation over 21 days, as shown by flow cytometry analysis. Moreover, via the expression of specific cardiac biomarkers, cardiac-specific cell functionality was confirmed. Our study depicted the heterocellular cardiac cell interactions, which is extremely important for the maintenance of normal physiology of the cardiac wall in vivo and significantly increased over a period of 21 days in in vitro. This 3D bioprinted “cardiac organoid” model can be adopted to simulate cardiac environments in which cellular crosstalk in diseased pathologies like cardiac atrophy can be studied in vitro and can further be used for drug cytotoxicity screening or underlying disease mechanisms.

Ni Fang,1,2,* Jia Liu,1,* Jingxin Hou,1,2 Yixin Zhong,1,2 Ying Luo,1,2 Liu Hu,1,2 Wenli Zhang,1,2 Junrui Wang,1,2 Jie Xu,1 Jun Zhou,1 Yu Zhang,1 Haitao Ran,2 Dajing Guo1 1Department of Radiology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China; 2Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dajing Guo, Email guodaj@163.comBackground: Arterial thrombosis is a serious threat to human health. Recently, many thrombus-targeted nanoparticles (NPs) have been constructed for detecting thrombi or monitoring thrombolysis, but their thrombus-targeting performance is limited. Considering this drawback, we designed a specific bionic system with enhanced thrombus-targeting ability.Materials and Methods: In the bionic system, gelatin was chosen as a carrier, and Fe3O4 served as a magnetic navigation medium and a magnetic resonance (MR) imaging agent. The CREKA peptide, which targets fibrin, was conjugated to the surface of gelatin to prepare targeted NPs (TNPs), which were then engulfed by macrophages to construct the bionic system. At the targeted site, the bionic system released its interior TNPs under low-intensity focused ultrasound (LIFU) irradiation. Moreover, the targeting performance was further improved by the conjugated CREKA peptide.Results: In this study, we successfully constructed a bionic system and demonstrated its targeting ability in vitro and in vivo. The results indicated that most TNPs were released from macrophages under LIFU irradiation at 2 W/cm2 for 10 min in vitro. Additionally, the enhanced thrombus-targeting ability, based on the natural tropism of macrophages toward inflammatory thrombi, magnetic navigation and the CREKA peptide, was verified ex vivo and in vivo. Moreover, compared with the bionic system group, the group treated with TNPs had significantly decreased liver and spleen signals in MR images and significantly enhanced liver and spleen signals in fluorescence images, indicating that the bionic system is less likely to be cleared by the reticuloendothelial system (RES) than TNPs, which may promote the accumulation of the bionic system at the site of the thrombus.Conclusion: These results suggest that the magnet-guided bionic system with LIFU responsiveness is an excellent candidate for targeting thrombi and holds promise as an innovative drug delivery system for thrombolytic therapy.Keywords: bionic system, low-intensity focused ultrasound, thrombus, magnetic navigation, macrophage

BACKGROUND Postoperative prolonged air leakage is a frequent complication after lung resection. We have developed a new sealant based on a hydrophobically modified Alaska pollock-derived gelatin (ApGltn) sealant. The purpose of this study was to evaluate the adhesive strength of the ApGltn sealant in comparison with a fibrin sealant using a new spray system in ex vivo and in vivo models. METHODS Pleural defects in ex vivo and in vivo porcine models were created, to which the ApGltn sealant or the fibrin sealant was applied. The pressure resistance was assessed with a stepwise increase in airway pressure to confirm air leakage from the sealing site. Tissue samples covered with each sealant were obtained for histologic assessment. RESULTS In the ex vivo experiment, the leak pressures of the ApGltn sealant were significantly greater than those of the fibrin sealant (102.94 ± 15.6 cm H2O and 28.37 ± 5.1 cm H2O, respectively) (P < .01). In the in vivo experiment, the leak pressures of the ApGltn sealant were also significantly greater than those of the fibrin sealant (68.82 ± 18.04 cm H2O and 43.33 ± 7.13 cm H2O, respectively) (P = .043). The histologic examination confirmed that the ApGltn sealant adhered tightly to both the pleura and the surface of the pleural defect. CONCLUSIONS The ApGltn sealant has sufficiently high adhesive quality in ex vivo and in vivo porcine lungs, which could be considered suitable and effective for use in the prevention of air leakage from the lungs.

Combined injectable cell-laden microspheres and angiogenesis approaches are promising for functional vascularized endodontic regeneration. However, advanced microsphere designs and production techniques that benefit practical applications are rarely developed. Herein, gelatin methacryloyl (GelMA)-alginate core-shell microcapsules were fabricated to co-encapsulate human dental pulp stem cells (hDPSCs) and human umbilical vein endothelial cells (HUVECs) based on a coaxial electrostatic microdroplet technique. This technique enables high-throughput production, convenient collection, and minimal material waste. The average diameter of core-shell microcapsules was ∼359 µm, and that of GelMA cores was ∼278 µm. There were higher proliferation rates for hDPSCs and HUVECs co-encapsulated in the GelMA cores than for hDPSCs or HUVECs monoculture group. HUVECs assembled to form 3D capillary-like networks in co-culture microcapsules. Moreover, HUVECs promoted the osteo/odontogenic differentiation of hDPSCs in microcapsules. After 14 days of cultivation, prevascularized microtissues formed in microcapsules that contained abundant deposited extracellular matrix (ECM); no microcapsule aggregation occurred. In vivo studies confirmed that better microvessel formation and pulp-like tissue regeneration occurred in the co-culture group than in hDPSCs group. Thus, an effective platform for prevascularization microtissue preparation was proposed and showed great promise in endodontic regeneration and tissue engineering applications. STATEMENT OF SIGNIFICANCE: Cell-laden microspheres combined with the proangiogenesis approach are promising in endodontic regeneration. We proposed GelMA-alginate core-shell microcapsules generated via the coaxial electrostatic microdroplet (CEM) method, which utilizes a double-lumen needle to allow for core-shell structures to form. The microcapsules were used for co-culturing hDPSCs and HUVECs to harvest large amounts of prevascularized microtissues, which further showed improved vascularization and pulp-like tissue regeneration in vivo. This CEM method and the microcapsule system have advantages of high-throughput generation, convenient collection, and avoid aggregation during long-term culturing. We proposed a high-effective platform for mass production of prevascularized microtissues, which exhibit great promise in the clinical transformation of endodontic regeneration and other applications in regenerative medicine.