Polyethylene Glycol-based Hydrogel Research Articles

Bacteria encapsulation into polyethylene glycol hydrogels using Michael-type addition reactions

AbstractHydrogel materials can be used to integrate bacteria cells into biohybrid systems. Here, we investigate the use of polyethylene glycol-based hydrogels that employ different Michael-type addition crosslinking chemistries, including thiol-acrylate, thiol-vinyl sulfone, and thiol-maleimide click reactions, for covalent hydrogel network formation and bacteria encapsulation. All crosslinking chemistries generated hydrogels that provided stable encapsulation and culture of Bacillus subtilis; however, significant differences in cell viability and cell morphology after encapsulation were identified. Thiol-acrylate hydrogels provided the highest cell viability and favored encapsulation of single cells, while thiol-maleimide hydrogels had the lowest cell viability and favored encapsulation of larger aggregates. These findings demonstrate the impact of crosslinking strategies for encapsulation of microorganisms into hydrogel networks and suggest that thiol-acrylate chemistries are favorable for many applications. Graphical abstract

Rapid in situ forming PEG hydrogels for mucosal drug delivery.

In situ gelling polymeric biomaterials have proven useful as drug delivery vehicles to enable sustained release at sites of disease or injury. However, if delivered to mucosal tissues, such as the eyes, nose, gastrointestinal, and cervicovaginal tract, these gels must also possess the ability to adhere to an epithelium coated in mucus. Towards this end, we report a new rapid in situ gelling polyethylene glycol-based hydrogel. Unlike other chemistries that enable rapid gel formation which form via irreversible covalent bonds, we use a bio-reducible linker allowing the gels to be naturally degraded over several days once administered. We identified a set of 6 lead formulations, which rapidly form into disulfide-linked PEG hydrogels in 30 seconds or less. These rapidly forming PEG hydrogels were also able to conform and adhere to mucosal tissues via PEG-mucin entanglements and hydrogen bonding. Controlled release of protein-based cargoes from the PEG gels was achieved over several hours whereas 40 nm nanoparticle-based cargos were retained over 24 hours. We also found these rapid in situ forming PEG gels were well-tolerated by mammalian cells. These studies support further testing and development of rapid in situ forming PEG gels for drug delivery to improve therapeutic retention and efficacy at mucosal sites.

Optical redox imaging to screen synthetic hydrogels for stem cell-derived cardiomyocyte differentiation and maturation.

Heart disease is the leading cause of death in the United States, yet research is limited by the inability to culture primary cardiac cells. Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (iPSCs) are a promising solution for drug screening and disease modeling. Induced pluripotent stem cell-derived CM (iPSC-CM) differentiation and maturation studies typically use heterogeneous substrates for growth and destructive verification methods. Reproducible, tunable substrates and touch-free monitoring are needed to identify ideal conditions to produce homogenous, functional CMs. We generated synthetic polyethylene glycol-based hydrogels for iPSC-CM differentiation and maturation. Peptide concentrations, combinations, and gel stiffness were tuned independently. Label-free optical redox imaging (ORI) was performed on a widefield microscope in a 96-well screen of gel formulations. We performed live-cell imaging throughout differentiation and early to late maturation to identify key metabolic shifts. Label-free ORI confirmed the expected metabolic shifts toward oxidative phosphorylation throughout the differentiation and maturation processes of iPSC-CMs on synthetic hydrogels. Furthermore, ORI distinguished high and low differentiation efficiency cell batches in the cardiac progenitor stage. We established a workflow for medium throughput screening of synthetic hydrogel conditions with the ability to perform repeated live-cell measurements and confirm expected metabolic shifts. These methods have implications for reproducible iPSC-CM generation in biomanufacturing.

Abstract 305: Bioinspired synthetic hydrogel in pancreatic cancer organoid matrix modeling

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality with a primary hallmark, including dense collagen matrix in the desmoplastic stroma. Organoid technologies often rely on commercially available EHS mouse sarcoma matrix materials, and it remains uncertain how batch-to-batch variability of this matrix impacts the consistency of cancer signaling. Here, we present a novel photo-activated hydrogel tuned to the properties of the desmoplastic stroma in PDAC organoid cultures. Method: We designed multiple synthetic hydrogel materials with tunable mechanical properties, including SP-139 (Stem Pharm, Inc), a polyethylene glycol-based hydrogel functionalized with norbornene and formed with both degradable and non-degradable crosslinking peptides and a cell adhesion peptide (CRGDS). We used rheometry to measure the elastic modulus of the polymerized hydrogel after visible light photoactivation (395 nm) and expanded multiple cancer organoid cultures. RNAseq was performed from patient-derived xenografts to expanded organoids across matrix designs (Cultrex® v. SP-139) and analyzed by GSVA pathway analyses. Result: We optimized the ratio of non-degradable v. degradable crosslinking peptide to support culture expansion and enzymatic digestion with dispase II (125 µg/mL) and collagenase II (1 mg/mL). Using rheometry, SP-139 at 75% v/v had increased elastic modulus versus Cultrex RGF BME matrix Type 2 at 100% v/v (4992±76.3 v. 68.4±5.6 Pa, p<0.0001). Phenotypic growth was confirmed across serial passages (>8) and a diversity of gastrointestinal cancer types (n=5). Baseline growth rates were identical over 48h between SP-139 (75% v/v) and Cultrex (50% v/v) (+13.4% v. +13.0, p=0.75). Growth remained consistent for SP-139 yet increased with Cultrex at interval of 48-96h (+12.9% SP-139 v +22.4% Cultrex, p<0.005) and interval of 96-144h (+13.6% SP-139 v +24.0% Cultrex®, p<0.0001). Therapeutic response was assessed using 3D CellTiter-Glo® using gemcitabine 100 µM (24h) with comparable inhibition of normalized cell viability in SP-139 v. Cultrex® (35.4±1.9% v. 52.3±6.5%, n.s.) and qualitatively with viability staining using calcein AM and Caspase 3/7FITC. RNAseq revealed Cultrex, when compared to SP-139, yielded down regulation of epoxygenase p450 pathways (padj<0.012) and negative regulation of the p38 MAP kinase cascade (padj<0.048). Conclusions: Functionalized PEG-based synthetic hydrogel matrix materials can be tuned for physical properties to mimic cancer tissue microenvironments more accurately. SP-139, designed to mimic the desmoplastic stroma of the pancreatic cancer microenvironment, has favorable properties including controlled growth rates and compatibility with high content imaging by luminescence and fluorescence. RNAseq pathway analysis shows SP-139 maintains pathways of p450 and MAP kinase signaling of importance with therapeutic resistance. Citation Format: Md Shahadat Hossan, Austin Stram, Ethan Samuel Lin, Sean McIlwain, Connie Lebakken, William Richards, Jeremy D. Kratz. Bioinspired synthetic hydrogel in pancreatic cancer organoid matrix modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 305.

Development of Polyethylene Glycol-based Hydrogels Optimized for In Vitro 3D Culture of HepG2 Hepatocarcinoma Cells.

We report an in vitro three-dimensional (3D) culture system optimized for the growth of HepG2 hepatocarcinoma cells. The 3D culture system was fabricated based on polyethylene glycol (PEG)-based hydrogels; their mechanical strength was controlled by differences in the arm number and concentration of PEG-vinylsulfone. Moreover, cellular growth was evaluated after culturing HepG2 cells in PEG-based hydrogels with various mechanical strengths. HepG2 cell culture in the 3D PEG-based hydrogels induced the formation of spherical colonies. Moreover, the highest number of spherical colonies formed from HepG2 cells at the single-cell level, and the formation of spherical colonies with a uniform size was observed in HepG2 cells cultured in 5% (w/v) 8-arm PEG-based hydrogels. 5% (w/v) 8-arm PEG-based hydrogels may be developed as a 3D culture system optimized for stimulating the in vitro growth of HepG2 cells.

A user's guide to degradation testing of polyethylene glycol-based hydrogels: From in vitro to in vivo studies.

Poly(ethylene glycol) (PEG)-based hydrogels have gained significant attention in the field of biomedical applications due to their versatility and antifouling properties. Acrylate-derivatized PEG hydrogels (PEGDA) are some of the most widely studied hydrogels; however, there has been debate around the degradation mechanism and predicting resorption rates. Several factors influence the degradation rate of PEG hydrogels, including backbone and endgroup chemistry, macromer molecular weight, and polymer concentration. In addition to hydrogel parameters, it is necessary to understand the influence of biological and environmental conditions (e.g., pH and temperature) on hydrogel degradation. Rigorous methods for monitoring degradation in both in vitro and in vivo settings are also critical to hydrogel design and development. Herein, we provide guidance on tailoring PEG hydrogel chemistry to achieve target hydrolytic degradation kinetics for both resorbable and biostable applications. A detailed overview of accelerated testing methods and hydrogel degradation characterization is provided to aid researchers in experimental design and interpreting in vitro-in vivo correlations necessary for predicting hydrogel device performance.

A colorimetric biosensor based on a biodegradable fluidic device capable of efficient saliva sampling and salivary biomarker detection

The use of saliva as a diagnostic biofluid offers many advantages over traditional blood-based diagnostics, and has the potential to revolutionize the field of point-of-care and personalized medicine. However, there remains a strong demand for precise and convenient saliva sampling and an all-in-one system that can achieve saliva sample loading and biomarker detection in a patient-friendly, easy-to-use, and cost-effective manner. In this study, we developed a biodegradable fluidic device for use in point-of-care diagnostics using saliva as a sample biofluid. The device comprised a sample loading zone and a detection zone connected through channels. A chitosan sponge was used to sample artificial saliva owing to its large absorption capacity and ability to release absorbed saliva, and polyethylene glycol-based hydrogel entrapping enzymes and dyes were used as the sensing module for the colorimetric detection of target biomarkers. When a saliva-absorbed chitosan sponge was inserted into the loading zone and squeezed, the absorbed saliva was released from the sponge and moved to the detection zone containing the hydrogel-based sensing module, where it initiated an enzyme-catalyzed reaction and subsequently induced a color change in the hydrogel. The enzyme-based detection of glucose and creatinine in a clinically useful concentration range confirmed the effectiveness of the proposed fluidic system. The proposed system enabled the quantitative detection of glucose and creatinine both spectrophotometrically and via smartphone-based analysis, highlighting its potential in point-of-care diagnostics.

Glioblastoma spheroid growth and chemotherapeutic responses in single and dual-stiffness hydrogels.

Glioblastoma (GBM) is the deadliest brain tumor for which there is no cure. Bioengineered GBM models, such as hydrogel-encapsulated spheroids, that capture both cell-cell and cell-matrix interactions could facilitate testing of much needed therapies. Elucidation of specific microenvironment properties on spheroid responsiveness to therapeutics would enhance the usefulness of GBM models as predictive drug screening platforms. Here, GBM spheroids consisting of U87 or patient-derived GBM cells were encapsulated in soft (∼1 kPa), stiff (∼7 kPa), and dual-stiffness polyethylene glycol-based hydrogels, with GBM spheroids seeded at the stiffness interface. Spheroids were cultured for 7 days and examined for viability, size, invasion, laminin expression, hypoxia, proliferation, and response to the chemotherapeutic temozolomide (TMZ). We noted excellent cell viability in all hydrogels, and higher infiltration in soft compared to stiff hydrogels for U87 spheroids. In dual gels spheroids mostly infiltrated away from the stiffness interface with minimal crossing over it and some individual cell migration along the interface. U87 spheroids were equally responsive to TMZ in the soft and stiff hydrogels, but cell viability in the spheroid periphery was higher than the core for stiff hydrogels whereas the opposite was true for soft hydrogels. HIF1A expression was higher in the core of spheroids in the stiff hydrogels, while there was no difference in cell proliferation between spheroids in the stiff vs soft hydrogels. Patient-derived GBM spheroids did not show stiffness-dependent drug responses. U87 cells showed similar laminin expression in soft and stiff hydrogels with higher expression in the spheroid periphery compared to the core. Our results indicate that microenvironment stiffness needs to be considered in bioengineered GBM models including those designed for use in drug screening applications. STATEMENT OF SIGNIFICANCE: Recent work on tumor models engineered for use in drug screening has highlighted the potential of hydrogel-encapsulated spheroids as a simple, yet effective platform that show drug responses similar to native tumors. It has also been shown that substrate stiffness, in vivo and in vitro, affects cancer cell responses to drugs. This is particularly important for glioblastoma (GBM), the deadliest brain cancer, as GBM cells invade by following the stiffer brain structures such as white matter tracks and the perivascular niche. Invading cells have also been associated with higher resistance to chemotherapy. Here we developed GBM spheroid models using soft, stiff and dual-stiffness hydrogels to explore the connection between substrate stiffness, spheroid invasion and drug responsiveness in a controlled environment.

GelMA, Click-Chemistry Gelatin and Bioprinted Polyethylene Glycol-Based Hydrogels as 3D Ex Vivo Drug Testing Platforms for Patient-Derived Breast Cancer Organoids.

3D organoid model technologies have led to the development of innovative tools for cancer precision medicine. Yet, the gold standard culture system (Matrigel®) lacks the ability for extensive biophysical manipulation needed to model various cancer microenvironments and has inherent batch-to-batch variability. Tunable hydrogel matrices provide enhanced capability for drug testing in breast cancer (BCa), by better mimicking key physicochemical characteristics of this disease’s extracellular matrix. Here, we encapsulated patient-derived breast cancer cells in bioprinted polyethylene glycol-derived hydrogels (PEG), functionalized with adhesion peptides (RGD, GFOGER and DYIGSR) and gelatin-derived hydrogels (gelatin methacryloyl; GelMA and thiolated-gelatin crosslinked with PEG-4MAL; GelSH). Within ranges of BCa stiffnesses (1−6 kPa), GelMA, GelSH and PEG-based hydrogels successfully supported the growth and organoid formation of HR+,−/HER2+,− primary cancer cells for at least 2−3 weeks, with superior organoid formation within the GelSH biomaterial (up to 268% growth after 15 days). BCa organoids responded to doxorubicin, EP31670 and paclitaxel treatments with increased IC50 concentrations on organoids compared to 2D cultures, and highest IC50 for organoids in GelSH. Cell viability after doxorubicin treatment (1 µM) remained >2-fold higher in the 3D gels compared to 2D and doxorubicin/paclitaxel (both 5 µM) were ~2.75−3-fold less potent in GelSH compared to PEG hydrogels. The data demonstrate the potential of hydrogel matrices as easy-to-use and effective preclinical tools for therapy assessment in patient-derived breast cancer organoids.

Dye-labeled aromatic azides for multi-photon grafting

The synthesis of two dye-labeled azides via de-symmetrization of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone (BAC-M) with a copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) using fluorescent dyes is reported. An alkyne functionalized dansyl derivative and an alkyne functionalized perylene diimide derivative were used as the dyes. The photo-physical properties of these dye dyads are described, and their performance in multi-photon grafting onto polyethylene glycol-based hydrogels is investigated. While the dansyl-conjugated BAC derivate is well suited for multi-photon grafting with lasers operating at 800 nm, the perylene diimide-bearing dye does not give the desired result.Graphical abstract

Fabrication of swellable PEGylated hydrogel by free radical polymerization for controlled delivery of non-steroidal anti-inflammatory drug; characterization and statistical analysis

The main objective of the current research work was to fabricate polyethylene glycol-based hydrogels for the controlled delivery of Ketorolac. Polyethylene glycol was chemically cross-linked with acrylic acid using 2-hydroxyethyl methacrylate as a cross-linker with ammonium persulfate and sodium metabisulphite as initiators. To determine the efficiency of the synthesized system, it was subjected to various structural characterization, such as Fourier transform infrared spectroscopy, Differential scanning calorimetry, Thermogravimetric analysis, and Scanning electron microscopy. All the results obtained from structural characterizations confirmed a well-cross-linked, thermally stable, and a porous system. Swelling and in-vitro release studies performed in pH 1.2 and 7.4 showed pH responsiveness as more swelling and drug release were observed in pH 7.4 as compared to pH 1.2. The drug release was considered as non-Fickian transport from kinetic modeling and partially controlled by the viscoelastic relaxation of hydrogel. Sol-gel fraction depicted that gel content was increased as the concentrations of the polymer, monomer, and cross linker were increased. Similarly, the results obtained from stability studies confirmed a stable synthesized system. Moreover, statistical analysis was also employed for a better comparison of the swelling and in-vitro results.

Application of Hydrogels as Carrier in Tumor Therapy: A Review.

Cancer is one of the most intractable diseases in the world because of its high recurrence rate, high metastasis rate and high lethality rate. Traditional chemotherapy, radiotherapy and surgery have unsatisfactory therapeutic effects and cause many severe side effects at the same time. Hydrogel is a new type of biomaterial with the advantages of good biocompatibility and easy degradation, which can be used as a carrier of functional nanomaterials for tumor therapy. Herein, we represent the progress of hydrogels with different skeletons and their application as carrier in tumor treatment. The hydrogels are listed as polyethylene glycol-based hydrogels, chitosan-based hydrogels, peptide-based hydrogels, hyaluronic acid-based hydrogels, steroid-based hydrogels and other hydrogels by skeletons, and their properties, modifications and toxicities were introduced. Some representative applications of combined hydrogels with nanomaterial for chemotherapy, photodynamic therapy, photothermal therapy, sonodynamic therapy, chemodynamic therapy and synergistic therapy are highlighted.

Adhesive polyethylene glycol-based hydrogel patch for tissue repair

Polyethylene glycol (PEG)-based tissue glue has been widely used in surgery, but the sealants were weak in strength and could not be in place of sutures. This paper prepared a PEG-based tissue patch made of F127-DA hydrogel and PEG-DA as adhesive. For the patch adhesion on tissues, photoinitiator of lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP, 0.1 % w/v) and UV flashlight at 395 nm for 30 s irradiation was used. The adhesion energy on pig skin, lung, heart, liver, kidney and stomach was 85.33, 56.40, 75.56, 70.22, 66.67 and 36.89 N/m, indicating the well stitching to different tissues. The hydrogel patch could also seal the punched tissues to prevent the leakage of liquid or air. Finally, the patch showed good tissue compatibility after 2 days adhesion on pig skin. In this regard, the hydrogel patch is expected to repair the wounded tissues without suture, being a biocompatible adhesive for wound healing of various tissues.

Optimization of polyethylene glycol-based hydrogel rectal spacer for focal laser ablation of prostate peripheral zone tumor.

Focal Laser ablation therapy is a technique that exposes the prostate tumor to hyperthermia ablation and eradicates cancerous cells. However, due to the excessive heating generated by laser irradiation, there is a possibility of damage to the adjacent healthy tissues. This paper through in silico study presents a novel approach to reduce collateral effects due to heating by the placement of polyethylene glycol (PEG) spacer between the rectum and tumor during laser irradiation. The PEG spacer thickness is optimized to reduce the undesired damage at common laser power used in the clinical trials. Our study also encompasses novelty by conducting the thermal analysis based on the porous structure of prostate tumor. The thermal parameters and two thermal phase lags between the temperature gradient and the heat flux, are determined by considering the vascular network of prostate tumor. The Nelder-Mead algorithm is applied to find the minimum thickness of the PEG spacer. In the absence of the spacer, the predicted results for the laser power of 4W, 8W, and 12W show that the temperature of the rectum rises up to 58.6 °C, 80.4 °C, and 101.1 °C, while through the insertion of 2.59mm, 4mm, and 4.9mm of the PEG spacer, it dramatically reduces below 42 °C. The results can be used as a guideline to ablate the prostate tumors while avoiding undesired damage to the rectal wall during laser irradiation, especially for the peripheral zone tumors.

Immobilization of transgenic plant cells towards bioprinting for production of a recombinant biodefense agent.

Transgenic rice cells (Oryza sativa) producing recombinant butyrylcholinesterase (BChE) as a prophylactic/therapeutic against organophosphate nerve agent poisoning, cocaine toxicity, and neurodegenerative diseases like Alzheimer's were immobilized in a polyethylene glycol-based hydrogel. The cells were sustained for 14 days in the semi-solid matrix, undergoing a growth phase from days 0-6, a BChE production phase in sugar-free medium from days 6-12, and a growth/recovery phase from days 12-14. Throughout this period, the cells maintained similar viability to those in suspension cultures and displayed analogous sugar consumption trends. The rice cells in the hydrogel also produced a significant amount of active BChE, comparable to the levels produced in liquid cultures. A considerable fraction of this BChE was secreted into the media, allowing for easier product separation. To the best of our knowledge, this proof-of-concept is the first report of immobilization of recombinant plant cells for continuous production of high-value heterologous proteins. This work serves as a foundation for further investigation towards plant cell bioprinting and the development of a simple, efficient, robust, modular, and potentially field-deployable bioreactor system for the manufacture of biologics.

Plasma Pharmacokinetic Parameters of Dexamethasone Following Administration of a Dexamethasone Intracanalicular Insert in Healthy Adults.

PurposeIntracanalicular dexamethasone insert is a resorbable sustained-release polyethylene glycol-based hydrogel insert delivering a 0.4 mg tapered dose of dexamethasone for up to 30 days to the ocular surface. It is FDA-approved for treating inflammation and pain after ocular surgery. It has also been studied for ocular surface diseases such as allergic conjunctivitis. This study assessed the plasma pharmacokinetic (PK) parameters of dexamethasone following intracanalicular insertion.Patients and MethodsStudy subjects (N=16) were healthy adults. A dexamethasone insert was unilaterally placed into the canaliculus, and blood samples were obtained for analysis 1 hour prior to insertion and 1, 2, 4, 8, 16, 24 hours and 4, 8, 15, 22 and 29 days after insertion. Safety analyses included slit lamp and dilated fundus examinations, best corrected visual acuity, intraocular pressure (IOP) and adverse events (AEs).ResultsPlasma results were below the lower limit of quantitation (LLOQ) at all time points in five subjects (31.3%). Among subjects with quantifiable plasma concentrations, Cmax was <1 ng/mL (range, 0.05 to 0.81 ng/mL), AUC0-last ranged from 0.13 to 7.18 h∙ng/mL, and Tmax ranged from 4.0 to 163.0 hours. Mean (SD) IOP increased from 16.3 (1.4) mmHg at baseline to 19.3 (3.2) at Day 22 but returned to baseline after treatment. No changes occurred in dilated fundus, punctum, or visual acuity examinations.ConclusionThe dexamethasone 0.4 mg insert results in minimal systemic exposure following intracanalicular administration.

Elucidating the Molecular Mechanisms for the Interaction of Water with Polyethylene Glycol-Based Hydrogels: Influence of Ionic Strength and Gel Network Structure.

The interaction of water within synthetic and natural hydrogel systems is of fundamental importance in biomaterial science. A systematic study is presented on the swelling behavior and states of water for a polyethylene glycol-diacrylate (PEGDA)-based model neutral hydrogel system that goes beyond previous studies reported in the literature. Hydrogels with different network structures are crosslinked and swollen in different combinations of water and phosphate-buffered saline (PBS). Network variables, polyethylene glycol (PEG) molecular weight (MW), and weight fraction are positively correlated with swelling ratio, while “non-freezable bound water” content decreases with PEG MW. The presence of ions has the greatest influence on equilibrium water and “freezable” and “non-freezable” water, with all hydrogel formulations showing a decreased swelling ratio and increased bound water as ionic strength increases. Similarly, the number of “non-freezable bound water” molecules, calculated from DSC data, is greatest—up to six molecules per PEG repeat unit—for gels swollen in PBS. Fundamentally, the balance of osmotic pressure and non-covalent bonding is a major factor within the molecular structure of the hydrogel system. The proposed model explains the dynamic interaction of water within hydrogels in an osmotic environment. This study will point toward a better understanding of the molecular nature of the water interface in hydrogels.

Evaluation of a novel hydrogel intravascular embolization agent in a swine model of fatal uncontrolled solid organ hemorrhage and coagulopathy

IntroductionCurrent agents for the intravascular embolization of traumatic hemorrhage are used off-label and have been minimally studied with respect to their performance under differing coagulation conditions. We studied the hemorrhage control efficacy of a novel, liquid, polyethylene glycol-based hydrogel delivered as two liquid precursors that polymerize within the target vessel in a unique animal model of severe solid organ injury with and without dilutional coagulopathy. MethodsAnesthetized swine (n = 36, 45 ± 3 kg) had laparotomy and splenic externalization. Half underwent 50% isovolemic hemodilution with 6% hetastarch and cooling to 33°C-35°C (coagulopathic group). All animals had controlled 20 mL/kg hemorrhage and endovascular proximal splenic artery access with a 4F catheter via a right femoral sheath. Splenic transection and 5-minute free bleeding were followed by treatment (n = 5/group) with 5 mL of gelfoam slurry, three 6-mm coils, up to 6 mL of hydrogel, or no treatment (n = 3, control). Animals received 15 mL/kg plasma and were monitored for 6 hours with continuous blood loss measurement. ResultsCoagulopathy was successfully established, with coagulopathic animals having greater pretreatment blood loss and earlier mean time to death regardless of the treatment group. All control animals died within 100 minutes. Overall survival without coagulopathy was 5/5 for hydrogel, 4/5 for coil, and 3/5 for gelfoam. With coagulopathy, one hydrogel animal survived to the end of the experiment, with 2/4 hydrogel deaths occurring in the final hour of observation. In noncoagulopathic animals, hydrogel demonstrated improved survival time (P < .01) and post-treatment blood loss (1.46 ± 0.8 mL/kg) over controls (18.8 ± 0.7, P = .001), gelfoam (4.7 ± 1.3, P > .05), and coils (4.6 ± 1.5, P > .05). In coagulopathic animals, hydrogel had improved survival time (P = .003) and decreased blood loss (4.2 ± 0.8 mL/kg) compared with control (20.4 ± 4.2, P = .003). ConclusionsThe hydrogel demonstrated equivalent hemorrhage control performance to standard treatments under noncoagulopathic conditions and improved performance in the face of dilutional coagulopathy. This agent should be explored as a potential preferable treatment for the embolization of traumatic solid organ and other injuries. (JVS–Vascular Science 2021;2:43-51.) Clinical RelevanceIn a translational model of severe solid organ injury hemorrhage with and without coagulopathy, a novel hydrogel transarterial embolization agent demonstrated equivalent hemorrhage control performance to standard agents under noncoagulopathic conditions and improved performance in the face of dilutional coagulopathy. This agent represents a promising future treatment for the embolization of traumatic solid organ and other injuries.

Segmental long bone regeneration guided by degradable synthetic polymeric scaffolds.

ABSTRACTRecent developments in synthetic bone grafting materials and adjuvant therapeutic agents have opened the door to the regenerative reconstruction of critical-size long bone segmental defects resulting from trauma, osteoporotic fractures or tumour resections. Polymeric scaffolds with controlled macroporosities, degradability, useful surgical handling characteristics, and the ability to deliver biotherapeutics to promote new bone ingrowth have been developed for this challenging orthopaedic application. This review highlights major classes of degradable synthetic polymers and their biomineral composites, including conventional and amphiphilic polyesters, polyanhydrides, polycarbonates, and polyethylene glycol-based hydrogels, that have been explored for the regenerative reconstruction of critical-size long bone segmental defects over the past two decades. The pros and cons of these synthetic scaffold materials are presented in the context of enabling or impeding the functional (mechanical and radiographic) repair of a long bone segmental defect, with the long bone regeneration outcomes compared with healthy long bone controls or results achieved with current grafting standards.

Polyethylene glycol-based hydrogel rectal spacers for prostate brachytherapy: a systematic review with a focus on technique

IntroductionRadiation dose to the rectum in prostate brachytherapy (PBT) can be reduced by the use of polyethylene glycol (PEG) hydrogel spacers. This reduces the rate of rectal toxicity and allows dose escalation to the prostate. Our objectives were to provide an overview of technique for injection of a PEG hydrogel spacer, reduction in rectal dosimetry, gastrointestinal toxicity and potential complications.MethodsWe systematically reviewed the role of PEG hydrogel spacers in PBT using the Cochrane and PRISMA methodology for all English-language articles from January 2013 to December 2019. Data was extracted for type of radiotherapy, number of patients, type of PEG-hydrogel used, mean prostate-rectum separation, rectal dosimetry, acute and late GI toxicity, procedure-related complications and the technique used for hydrogel insertion.ResultsNine studies (671 patients and 537 controls) met our inclusion criteria. Of these 4 used DuraSeal® and 5 used SpaceOAR®. The rectal spacing achieved varied between 7.7-16 mm. Failure of hydrogel insertion was seen only in 12 patients, mostly related to failure of hydrodissection in patients undergoing salvage PBT. Where reported, the rectal D2 cc was reduced by between 21.6 and 52.6% and the median rectal V75% cc was reduced by between 91.8–100%. Acute GI complications were mostly limited to grade 1 or 2 toxicity (n = 153, 33.7%) with low levels of grade 3 or 4 toxicity (n = 1, 0.22%). Procedure-related complications were limited to tenesmus (0.14%), rectal discomfort (1.19%), and bacterial prostatitis (0.44%).ConclusionsPEG hydrogel spacers are safe to insert. Gel insertion is easy, fast and has a low rate of failure. These studies convincingly demonstrate a significant reduction in rectal dosimetry. Although the results of spacers in reducing rectal toxicity is promising, these need to be confirmed in prospective randomised trial.