ABSTRACT
Conductive hydrogels have gained interest in biomedical applications and soft electronics. To tackle the challenge of ionic hydrogels falling short of desired mechanical properties in previous studies, our investigation aimed to understand the pivotal structural factors that impact the conductivity and mechanical behavior of polyethylene glycol (PEG)-based hydrogels with ionic conductivity. Polyether urethane diacrylamide (PEUDAm), a functionalized long-chain macromer based on PEG, was used to synthesize hydrogels with ionic conductivity conferred by incorporating ions into the liquid phase of hydrogel. The impact of salt concentration, water content, temperature, and gel formation on both mechanical properties and conductivity was characterized to establish parameters for tuning hydrogel properties. To further expand the range of conductivity available in these ionic hydrogels, 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) was incorporated as a single copolymer network or double network configuration. As expected, conductivity in these ionic gels was primarily driven by ion diffusivity and charge density, which was dependent on hydrogel network formation and swelling. Copolymer network structure had minimal effect on the conductivity which was primarily driven by counter-ion equilibrium; however, the mechanical properties and equilibrium swelling was strongly dependent on network structure. The structure-property relationships elucidated here enables the rationale design of this new double network hydrogel to achieve target properties for a broad range of applications.
ABSTRACT
Stem cell therapy and skin substitutes address the stalled healing of chronic wounds in order to promote wound closure; however, the high cost and regulatory hurdles of these treatments limit patient access. A low-cost method to induce bioactive healing has the potential to substantially improve patient care and prevent wound-induced limb loss. A previous study reported that bioactive factors derived from apoptotic-like mesenchymal stem cells (MSCs) demonstrated anti-inflammatory and proangiogenic effects and improved ischemic muscle regeneration. In this work, these MSC-derived bioactive factors were loaded into a hydrogel foam to harness immunomodulatory and angiogenic properties from MSC components to facilitate chronic wound healing without the high cost and translational challenges of cell therapies. After incorporation of bioactive factors, the hydrogel foam retained high absorbency, moisture retention, and target water vapor transmission rate. High loading efficiency was confirmed and release studies indicated that over 90% of loaded factors were released within 24 h. Ethylene oxide sterilization and 4-week storage did not affect the bioactive factor release profile or physical properties of the hydrogel foam dressing. Bioactivity retention of the released factors was also confirmed for as-sterilized, 4°C-stored, and -20°C-stored bioactive hydrogel foams as determined by relevant gene expression levels in treated pro-inflammatory (M1) macrophages. These results support the use of the bioactive dressings as an off-the-shelf product. Overall, this work reports a new method to achieve a first-line wound dressing with the potential to reduce persistent inflammation and promote angiogenesis in chronic wounds.
Subject(s)
Bandages , Hydrogels , Mesenchymal Stem Cells , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Hydrogels/chemistry , Hydrogels/pharmacology , Animals , Humans , Mice , Angiogenesis Inducing Agents/pharmacology , Wound Healing/drug effects , Neovascularization, Physiologic/drug effects , Immunologic Factors/pharmacologyABSTRACT
A major challenge in chronic wound treatment is maintaining an appropriate wound moisture balance throughout the healing process. Wound dehydration hinders wound healing due to impeded molecule transport and cell migration with associated tissue necrosis. In contrast, wounds that produce excess fluid contain high levels of reactive oxygen species and matrix metalloproteases that impede cell recruitment, extracellular matrix reconstruction, and angiogenesis. Dressings are currently selected based on the relative amount of wound exudate with no universal dressing available that can maintain appropriate wound moisture balance to enhance healing. This work aimed to develop a high porosity poly(ethylene glycol) diacrylate hydrogel foam that can both rapidly remove exudate and provide self-tuning moisture control to prevent wound dehydration. A custom foaming device was used to vary hydrogel foam porosity from 25% to 75% by adjusting the initial air-to-solution volume ratio. Hydrogel foams demonstrated substantial improvements in water uptake volume and rate as compared to bulk hydrogels while maintaining similar hydration benefits with slow dehydration rates. The hydrogel foam with the highest porosity (~75%) demonstrated the greatest water uptake and rate, which outperformed commercial dressing products, Curafoam® and Silvercel®, in water absorption, moisture retention, and exudate management. Investigation of the water vapor transmission rates of each dressing at varied hydration levels was characterized and demonstrated the dynamic moisture-controlling capability of the hydrogel foam dressing. Overall, the self-tuning moisture control of this hydrogel foam dressing holds great promise to improve healing outcomes for both dry and exudative chronic wounds.
Subject(s)
Bandages , Dehydration , Humans , Porosity , Biocompatible Materials , HydrogelsABSTRACT
Medical image segmentation prerequisite for numerous clinical needs is a critical step in biomedical image analysis. The U-Net framework is one of the most popular deep networks in this field. However, U-Net's successive pooling and downsampling operations result in some loss of spatial information. In this paper, we propose a U-shaped context residual network, called UCR-Net, to capture more context and high-level information for medical image segmentation. The proposed UCR-Net is an encoder-decoder framework comprising a feature encoder module and a feature decoder module. The feature decoder module contains four newly proposed context attention exploration(CAE) modules, a newly proposed global and spatial attention (GSA) module, and four decoder blocks. We use the proposed CAE module to capture more multi-scale context features from the encoder. The proposed GSA module further explores global context features and semantically enhanced deep-level features. The proposed UCR-Net can recover more high-level semantic features and fuse context attention information from CAE and global and spatial attention information from GSA module. Experiments on the retinal vessel, femoropopliteal artery stent, and polyp datasets demonstrate that the proposed UCR-Net performs favorably against the original U-Net and other advanced methods.
Subject(s)
Femoral Artery , Image Processing, Computer-Assisted , Humans , Disease Progression , Retinal Vessels , SemanticsABSTRACT
Collagens are the major structural component in animal extracellular matrices and are critical signaling molecules in various cell-matrix interactions. Its unique triple helical structure is enabled by tripeptide Gly-X-Y repeats. Understanding of sequence requirements for animal-derived collagen led to the discovery of prokaryotic collagen-like protein in the early 2000s. These prokaryotic collagen-like proteins are structurally similar to mammalian collagens in many ways. However, unlike the challenges associated with recombinant expression of mammalian collagens, these prokaryotic collagen-like proteins can be readily expressed in E. coli and are amenable to genetic modification. In this review article, we will first discuss the properties of mammalian collagen and provide a comparative analysis of mammalian collagen and prokaryotic collagen-like proteins. We will then review the use of prokaryotic collagen-like proteins to both study the biology of conventional collagen and develop a new biomaterial platform. Finally, we will describe the application of Scl2 protein, a streptococcal collagen-like protein, in thromboresistant coating for cardiovascular devices, scaffolds for bone regeneration, chronic wound dressing and matrices for cartilage regeneration.
ABSTRACT
The immune microenvironment induced by biomaterials played vital roles in bone regeneration. Hydroxyapatite (HA) and its ion-substituted derivates represent a large class of core inorganic materials for bone tissue engineering. Although ion substitution was proved to be a potent way to grant HA more biological functions, few studies focused on the immunomodulatory properties of ion-doped HA. Herein, to explore the potential osteoimmunomodulatory effects of ion-doped HA, zinc and strontium co-assembled into HA through a collagen template biomimetic way (ZnSr-Col-HA) was successfully achieved. It was found that ZnSr-Col-HA could induce a favorable osteo-immune microenvironment by stimulating macrophages. Furthermore, ZnSr-Col-HA demonstrated a procedural promoting effect on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. Specifically, the osteo-immune microenvironment acted as a dominant factor in promoting osteogenic gene expressions at the early stage through OSM signal pathway. Whereas the direct stimulating effects on BMSCs by Zn2+/Sr2+ were more effectively at the later stage with Nfatc1/Maf and Wnt signals activated. In vivo study confirmed strong promoting effects of ZnSr-Col-HA on critical-sized cranial defect repair. The current study indicated that such a combined biomaterial design philosophy of dual ion-doping and biomimetic molecular co-assembly to endow HA applicable osteoimmunomodulatory characteristics might bring up a new cutting-edge concept for bone regeneration study.
ABSTRACT
The high incidence of osteomyelitis associated with critical-sized bone defects raises clinical challenges in fracture healing. Clinical use of antibiotic-loaded bone cement as an adjunct therapy is limited by incompatibility with many antimicrobials, sub-optimal release kinetics, and requirement of surgical removal. Furthermore, overuse of antibiotics can lead to bacterial modifications that increase efflux, decrease binding, or cause inactivation of the antibiotics. Herein, we compared the efficacy of gallium maltolate, a new metal-based antimicrobial, to gentamicin sulfate released from electrospun poly(lactic-co-glycolic) acid (PLGA) wraps in the treatment of osteomyelitis. In vitro evaluation demonstrated sustained release of each antimicrobial up to 14 days. A Kirby Bauer assay indicated that the gentamicin sulfate-loaded wrap inhibited the growth of osteomyelitis-derived isolates, comparable to the gentamicin sulfate powder control. In contrast, the gallium maltolate-loaded wrap did not inhibit bacteria growth. Subsequent microdilution assays indicated a lower than expected sensitivity of the osteomyelitis strain to the gallium maltolate with release concentrations below the threshold for bactericidal activity. A comparison of the selectivity indices indicated that gentamicin sulfate was less toxic and more efficacious than gallium maltolate. A pilot study in a contaminated femoral defect model confirmed that the sustained release of gentamicin sulfate from the electrospun wrap resulted in bacteria density reduction on the surrounding bone, muscle, and hardware below the threshold that impedes healing. Overall, these findings demonstrate the efficacy of a resorbable, antimicrobial wrap that can be used as an adjunct or stand-alone therapy for controlled release of antimicrobials in the treatment of osteomyelitis.
Subject(s)
Bone Cements , Gentamicins , Organometallic Compounds , Osteomyelitis , Pyrones , Staphylococcal Infections , Staphylococcus aureus/metabolism , Animals , Bone Cements/chemistry , Bone Cements/pharmacology , Cell Line , Gentamicins/chemistry , Gentamicins/pharmacokinetics , Gentamicins/pharmacology , Male , Mice , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Osteomyelitis/drug therapy , Osteomyelitis/metabolism , Osteomyelitis/microbiology , Pyrones/chemistry , Pyrones/pharmacology , Rats , Rats, Sprague-Dawley , Staphylococcal Infections/drug therapy , Staphylococcal Infections/metabolismABSTRACT
The growth of bacterial biofilms on implanted medical devices causes harmful infections and device failure. Biofilm development initiates when bacteria attach to and sense a surface. For the common nosocomial pathogen Pseudomonas aeruginosa and many others, the transition to the biofilm phenotype is controlled by the intracellular signal and second messenger cyclic-di-GMP (c-di-GMP). It is not known how biomedical materials might be adjusted to impede c-di-GMP signalling, and there are few extant methods for conducting such studies. Here, we develop such a method. We allowed P. aeruginosa to attach to the surfaces of poly(ethylene glycol) diacrylate (PEGDA) hydrogels. These bacteria contained a plasmid for a green fluorescent protein (GFP) reporter for c-di-GMP. We used laser-scanning confocal microscopy to measure the dynamics of the GFP reporter for 3 h, beginning 1 h after introducing bacteria to the hydrogel. We controlled for the effects of changes in bacterial metabolism using a promoterless plasmid for GFP, and for the effects of light passing through different hydrogels being differently attenuated by using fluorescent plastic beads as 'standard candles' for calibration. We demonstrate that this method can measure statistically significant differences in c-di-GMP signalling associated with different PEGDA gel types and with the surface-exposed protein PilY1.
ABSTRACT
The ability to direct cell behavior has been central to the success of numerous therapeutics to regenerate tissue or facilitate device integration. Biomaterial scientists are challenged to understand and modulate the interactions of biomaterials with biological systems in order to achieve effective tissue repair. One key area of research investigates the use of extracellular matrix-derived ligands to target specific integrin interactions and induce cellular responses, such as increased cell migration, proliferation, and differentiation of mesenchymal stem cells. These integrin-targeting proteins and peptides have been implemented in a variety of different polymeric scaffolds and devices to enhance tissue regeneration and integration. This review first presents an overview of integrin-mediated cellular processes that have been identified in angiogenesis, wound healing, and bone regeneration. Then, research utilizing biomaterials are highlighted with integrin-targeting motifs as a means to direct these cellular processes to enhance tissue regeneration. In addition to providing improved materials for tissue repair and device integration, these innovative biomaterials provide new tools to probe the complex processes of tissue remodeling in order to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies.
ABSTRACT
Drug delivery to solid tumors is hindered by hydrostatic and physical barriers that limit the penetration of nanocarriers into tumor tissue. When exploiting the enhanced permeability and retention (EPR) effect for passive targeting of nanocarriers, the increased interstitial fluid pressure and dense extracellular matrix in tumors limits the distribution of the nanocarriers to perivascular regions. Previous strategies have shown that magnetophoresis enhances accumulation and penetration of nanoparticles into solid tumors. However, because magnetic fields fall off rapidly with distance from the magnet, these methods have been limited to use in superficial tumors. To overcome this problem, we have developed a system comprising two oppositely polarized magnets that enables the penetration of magnetic nanocarriers into more deeply seeded tumors. Using this method, we demonstrate a 5-fold increase in the penetration and a 3-fold increase in the accumulation of magnetic nanoparticles within solid tumors compared to EPR.
Subject(s)
Breast Neoplasms/diagnostic imaging , Nanoparticles/chemistry , Animals , Breast Neoplasms/pathology , Drug Carriers/chemistry , Drug Delivery Systems , Female , Magnetic Phenomena , Mice , Mice, Inbred BALB C , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/pathology , Particle Size , Surface PropertiesABSTRACT
Resorbable hydrogels have numerous potential applications in tissue engineering and drug delivery due to their highly tunable properties and soft tissue-like mechanical properties. The incorporation of esters into the backbone of poly(ethylene glycol) hydrogels has been used to develop libraries of hydrogels with tunable degradation rates. However, these synthetic strategies used to increase degradation rate often result in undesired changes in the hydrogel physical properties such as matrix modulus or swelling. In an effort to decouple degradation rate from other hydrogel properties, we inserted thio-ß esters into the poly(ethylene glycol)-diacrylate backbone to introduce labile bonds without changing macromer molecular weight. This allowed the number of hydrolytically labile thio-ß esters to be controlled through changing the ratios of this modified macromer to the original macromer without affecting network properties. The retention of hydrogel properties at different macromer ratios was confirmed by measuring gel fraction, swelling ratio, and compressive modulus. The tunable degradation profiles were characterized both in vitro and in vivo. Following confirmation of cytocompatibility after exposure to the hydrogel degradation products, the in vivo host response was evaluated in comparison to medical grade silicone. Collectively, this work demonstrates the utility and tunability of these hydrolytically degradable hydrogels for a wide variety of tissue engineering applications.
Subject(s)
Biocompatible Materials , Esters , Hydrogels , Polyethylene Glycols , Tissue Engineering , Animals , Biocompatible Materials/chemistry , Esters/chemistry , Female , Fibroblasts/cytology , Humans , Hydrogels/chemistry , Lymphocytes/cytology , Macrophages/cytology , Polyethylene Glycols/chemistry , Rats, Sprague-DawleyABSTRACT
Biofilm infections can consist of bacterial aggregates that are an order of magnitude larger than neutrophils, phagocytic immune cells that densely surround aggregates but do not enter them. Because a neutrophil is too small to engulf the entire aggregate, it must be able to detach and engulf a few bacteria at a time if it is to use phagocytosis to clear the infection. Current research techniques do not provide a method for determining how the success of phagocytosis, here defined as the complete engulfment of a piece of foreign material, depends on the mechanical properties of a larger object from which the piece must be removed before being engulfed. This article presents a step toward such a method. By varying polymer concentration or cross-linking density, the elastic moduli of centimeter-sized gels are varied over the range that was previously measured for Pseudomonas aeruginosa biofilms grown from clinical bacterial isolates. Human neutrophils are isolated from blood freshly drawn from healthy adult volunteers, exposed to gel containing embedded beads for 1 h, and removed from the gel. The percentage of collected neutrophils that contain beads that had previously been within the gels is used to measure successful phagocytic engulfment. Both increased polymer concentration in agarose gels and increased cross-linking density in alginate gels are associated with a decreased success of phagocytic engulfment. Upon plotting the percentage of neutrophils showing successful engulfment as a function of the elastic modulus of the gel to which they were applied, it is found that data from both alginate and agarose gels collapse onto the same curve. This suggests that gel mechanics may be impacting the success of phagocytosis and demonstrates that this experiment is a step toward realizing methods for measuring how the mechanics of a large target, or a large structure in which smaller targets are embedded, impact the success of phagocytic engulfment.
Subject(s)
Biofilms , Elastic Modulus , Phagocytosis , Adult , Alginates/chemistry , Cells, Cultured , Humans , Hydrogels/chemistry , Neutrophils/immunology , Neutrophils/microbiology , Pseudomonas aeruginosa/pathogenicity , Pseudomonas aeruginosa/physiology , Sepharose/chemistry , ViscosityABSTRACT
Chronic wounds are projected to reach epidemic proportions worldwide because of the aging population and the increasing incidence of diabetes. Despite extensive research, infection remains one of the leading sources of complications in chronic wounds, resulting in improper healing, biofilm formation, and lower extremity amputation. To address the limitations of standard treatments, we have developed a hydrogel wound dressing with self-tuning moisture control that incorporates a novel antimicrobial agent to eliminate and prevent infection. 3D-printing of a hydrogel dressing with dual porosity resulted in a new dressing with greater flexibility, increased water uptake, and more rapid swelling than bulk hydrogel dressings. Additionally, gallium maltolate (GaM) was incorporated into the dressing to investigate the efficacy of this antimicrobial agent. Loading profiles, release kinetics, and the bactericidal activity against Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus) of GaM were investigated in vitro to identify target profiles that supported infection control. Finally, GaM-loaded hydrogel dressings were evaluated in vivo, utilizing a murine splinted-wound model that was inoculated with S. aureus. In comparison to an untreated control, GaM dressings markedly reduced the wound bacterial load without compromising wound closure rates. Overall, this work demonstrates the utility of a 3D-printed hydrogel dressing as an antimicrobial dressing to control infection in chronic wounds.