Prosapia bicincta (Hemiptera: Cercopidae) abundance, plant associations, and impacts on groundcover in Hawai'i Island rangelands.

The twolined spittlebug, Prosapia bicincta (Say), is a major economic pest of forage grass and turfgrass. Prosapia bicincta was first detected in rangelands on Hawai'i Island in 2016 and has since spread to an estimated 72,000 ha in the North and South Kona districts. This study aimed to quantify P. bicincta abundance, plant associations, and impacts on groundcover over time. Monthly surveys of P. bicincta nymphs and adults were conducted from February 2018 to September 2022 along 17 established 100-m transects at 4 ranches located in Kona, Hawai'i Island, spanning an elevation gradient from 519 to 1,874 m above sea level (a.s.l.). Monitoring revealed P. bicincta occurs from 519 to 1,679 m a.s.l., primarily in Kikuyu grass (Cenchrus clandestinus (Hochst. ex Chiov.)) Morrone (Poales: Poaceae) pastures. Peaks in P. bicincta abundance coincided with the wet season, with most activity occurring from April to October and little to no activity between November and March. Mid elevation (1,000-1,300 m) transects had significantly higher mean P. bicincta abundance (126 nymphs/m2) relative to low (500-999 m) (64 nymphs/m2) and high elevations (>1,300 m) (20 nymphs/m2). Sites with the highest abundance of P. bicincta were also associated with the greatest decrease in mean grass cover (30%) and were replaced by forbs, bare ground, and shrubs. Grasses accounted for 72% of the total P. bicincta detections, with the remaining plants comprised of legumes (16%), sedges (6%), and forbs (6%). Twenty new P. bicincta plant associations were found. This information will help improve the effectiveness of management to suppress populations below economic thresholds.

Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

Hyaluronic Acid/Chondroitin Sulfate-Based Dynamic Thiol-Aldehyde Addition Hydrogel: An Injectable, Self-Healing, On-Demand Dissolution Wound Dressing.

Frequent removal and reapplication of wound dressings can cause mechanical disruption to the healing process and significant physical discomfort for patients. In response to this challenge, a dynamic covalent hydrogel has been developed to advance wound care strategies. This system comprises aldehyde functionalized chondroitin sulfate (CS-CHO) and thiolated hyaluronic acid (HA-SH), with the distinct ability to form in situ via thiol-aldehyde addition and dissolve on-demand via the thiol-hemithioacetal exchange reaction. Although rarely reported, the dynamic covalent reaction of thiol-aldehyde addition holds great promise for the preparation of dynamic hydrogels due to its rapid reaction kinetics and easy reversible dissociation. The thiol-aldehyde addition chemistry provides the hydrogel system with highly desirable characteristics of rapid gelation (within seconds), self-healing, and on-demand dissolution (within 30 min). The mechanical and dissolution properties of the hydrogel can be easily tuned by utilizing CS-CHO materials of different aldehyde functional group contents. The chemical structure, rheology, self-healing, swelling profile, degradation rate, and cell biocompatibility of the hydrogels are characterized. The hydrogel possesses excellent biocompatibility and proves to be significant in promoting cell proliferation in vitro when compared to a commercial hydrogel (HyStem® Cell Culture Scaffold Kit). This study introduces the simple fabrication of a new dynamic hydrogel system that can serve as an ideal platform for biomedical applications, particularly in wound care treatments as an on-demand dissolvable wound dressing.

An integrated single-cell RNA-seq map of human neuroblastoma tumors and preclinical models uncovers divergent mesenchymal-like gene expression programs.

BACKGROUND: Neuroblastoma is a common pediatric cancer, where preclinical studies suggest that a mesenchymal-like gene expression program contributes to chemotherapy resistance. However, clinical outcomes remain poor, implying we need a better understanding of the relationship between patient tumor heterogeneity and preclinical models. RESULTS: Here, we generate single-cell RNA-seq maps of neuroblastoma cell lines, patient-derived xenograft models (PDX), and a genetically engineered mouse model (GEMM). We develop an unsupervised machine learning approach ("automatic consensus nonnegative matrix factorization" (acNMF)) to compare the gene expression programs found in preclinical models to a large cohort of patient tumors. We confirm a weakly expressed, mesenchymal-like program in otherwise adrenergic cancer cells in some pre-treated high-risk patient tumors, but this appears distinct from the presumptive drug-resistance mesenchymal programs evident in cell lines. Surprisingly, however, this weak-mesenchymal-like program is maintained in PDX and could be chemotherapy-induced in our GEMM after only 24 h, suggesting an uncharacterized therapy-escape mechanism. CONCLUSIONS: Collectively, our findings improve the understanding of how neuroblastoma patient tumor heterogeneity is reflected in preclinical models, provides a comprehensive integrated resource, and a generalizable set of computational methodologies for the joint analysis of clinical and pre-clinical single-cell RNA-seq datasets.

Identifying MAGE-A4-positive tumors for TCR T cell therapies in HLA-A∗02-eligible patients.

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across North America and Europe. While HLA-A∗02:01 was the most frequent HLA-A∗02 allele, others (A∗02:02, A∗02:03, A∗02:06) considerably increased HLA eligibility in Hispanic, Black, and Asian populations. Overall, MAGE-A4 prevalence based on clinical trial enrollment was 26% (447/1,750) across 10 solid tumor types, and was highest in synovial sarcoma (70%) and lowest in gastric cancer (9%). The covariates were generally not associated with MAGE-A4 expression, except for patient age in ovarian cancer and histology in non-small cell lung cancer. This report shows the eligibility rate from biomarker screening for TCR T cell therapies and provides epidemiological data for future clinical development of MAGE-A4-targeted therapies.

Consensus recommendations for the use of novel antiretrovirals in persons with HIV who are heavily treatment-experienced and/or have multidrug-resistant HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy: An executive summary.

Treatment options are currently limited for persons with HIV-1 (PWH) who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. Three agents have been approved by the U.S. Food and Drug Administration (FDA) since 2018, representing a significant advancement for this population: ibalizumab, fostemsavir, and lenacapavir. However, there is a paucity of recommendations endorsed by national and international guidelines describing the optimal use (e.g., selection and monitoring after initiation) of these novel antiretrovirals in this population. To address this gap, a modified Delphi technique was used to develop these consensus recommendations that establish a framework for initiating and managing ibalizumab, fostemsavir, or lenacapavir in PWH who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. In addition, future areas of research are also identified and discussed in the main document.

Consensus recommendations for the use of novel antiretrovirals in persons with HIV who are heavily treatment-experienced and/or have multidrug-resistant HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy.

Treatment options are currently limited for persons with HIV-1 (PWH) who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. Three agents have been approved by the U.S. Food and Drug Administration (FDA) since 2018, representing a significant advancement for this population: ibalizumab, fostemsavir, and lenacapavir. However, there is a paucity of recommendations endorsed by national and international guidelines describing the optimal use (e.g., selection and monitoring after initiation) of these novel antiretrovirals in this population. To address this gap, a modified Delphi technique was used to develop these consensus recommendations that establish a framework for initiating and managing ibalizumab, fostemsavir, or lenacapavir in PWH who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. In addition, future areas of research are also identified and discussed.

Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFß inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors: Findings from a phase 1/1b study.

SAR439459 (SAR'459), a "second-generation" human anti-transforming growth factor beta (TGFß) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients.

An integrated single-cell RNA-seq map of human neuroblastoma tumors and preclinical models uncovers divergent mesenchymal-like gene expression programs.

Neuroblastoma is a common pediatric cancer, where preclinical studies suggest that a mesenchymal-like gene expression program contributes to chemotherapy resistance. However, clinical outcomes remain poor, implying we need a better understanding of the relationship between patient tumor heterogeneity and preclinical models. Here, we generated single-cell RNA-seq maps of neuroblastoma cell lines, patient-derived xenograft models (PDX), and a genetically engineered mouse model (GEMM). We developed an unsupervised machine learning approach ('automatic consensus nonnegative matrix factorization' (acNMF)) to compare the gene expression programs found in preclinical models to a large cohort of patient tumors. We confirmed a weakly expressed, mesenchymal-like program in otherwise adrenergic cancer cells in some pre-treated high-risk patient tumors, but this appears distinct from the presumptive drug-resistance mesenchymal programs evident in cell lines. Surprisingly however, this weak-mesenchymal-like program was maintained in PDX and could be chemotherapy-induced in our GEMM after only 24 hours, suggesting an uncharacterized therapy-escape mechanism. Collectively, our findings improve the understanding of how neuroblastoma patient tumor heterogeneity is reflected in preclinical models, provides a comprehensive integrated resource, and a generalizable set of computational methodologies for the joint analysis of clinical and pre-clinical single-cell RNA-seq datasets.

Vertical and temporal flight patterns of coffee berry borer (Coleoptera: Curculionidae) in Hawaii.

Coffee berry borer (Hypothenemus hampei Ferrari) (Coleoptera: Curculionidae) is the most damaging insect pest of coffee worldwide, causing significant losses in coffee yields and quality. Knowledge of vertical and temporal flight patterns in coffee berry borer could be used to optimize spray timing and precision targeting of areas within the coffee tree, which may be more susceptible. In the present study, we estimated the vertical distribution of coffee berry borer females using traps set at 1-m intervals up to 5 m in height. We also quantified coffee berry borer infestation in the low, mid, and high canopy and documented fruit availability. Temporal flight patterns were estimated using timer traps, and correlation analyses were conducted to determine the relationship between the timing of daily flight and weather variables. Across the 4 study sites, we observed that 77%-84% of the trap catch was at 1 m, 11%-20% was at 2 m, and 1%-4% was at 3-5 m in height. Fruit infestation was significantly higher in the low branches (35%) relative to the high branches (17%). Flight height remained the same year-round, regardless of fruit availability. Coffee berry borer flew in low numbers during the day and night but peaked from 12 to 4 PM. Daily flight was positively correlated with an increase in air temperature and wind speed and negatively correlated with relative humidity. Findings from this study suggest that pesticide sprays should target low- to mid-level branches at 1-2 m in height and aim to be conducted in the early afternoon when coffee berry borer are actively flying and most vulnerable to chemical controls.

Coffee berry borer (Coleoptera: Scolytidae) population dynamics across Hawaii Island's diverse coffee-growing landscape: optimizing location-specific pesticide applications.

A major challenge to area-wide management of coffee berry borer (Hypothenemus hampei Ferrari) (Coleoptera: Scolytidae) is understanding how a heterogeneous coffee-growing landscape affects coffee berry borer population dynamics across temporal and spatial scales. We examined coffee phenology, weather, coffee berry borer flight activity, infestation, coffee berry borer position within the fruit, and management across 14 commercial coffee farms from 2016 to 2018 on Hawaii Island to characterize variation among districts and elevations. Here we aim to determine whether the timing of pesticide applications might be optimized based on specific locations. We observed larger populations of coffee berry borer at low-elevation farms and in the Kona district compared to mid- and high-elevation farms and the Ka'u district. Temperature, relative humidity, and rainfall all differed significantly across districts and elevations. We also observed a trend of higher fruit production at low-elevation farms compared to high-elevation farms, and differences in the timing of fruit development. Infestation increased with higher pest pressure and air temperatures and reduced fruit availability early and late in the season. Lastly, the timing and number of management interventions varied among districts and elevations. Combining information on trap catch, infestation, coffee berry borer position, and plant phenology, we present an optimized pesticide spray schedule for each location and find that the number of sprays could be reduced by 33-75% in comparison to the existing integrated pest management recommendations while maintaining effective control. Implementing a coordinated area-wide approach refined by small-scale optimization will lead to improved management of coffee berry borer on individual farms and a reduction in pest pressure across the coffee-growing landscape.

Longitudinal Patterns of Multimorbidity in Gulf War Era Veterans With and Without Gulf War Illness.

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository (n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging.

RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity.

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

The importance of pharmacist engagement in diagnostic stewardship.

Diagnostic stewardship is increasingly recognized as a powerful tool to improve patient safety. Given the close relationship between diagnostic testing and antimicrobial misuse, antimicrobial stewardship (AMS) pharmacists should be key members of the diagnostic team. Pharmacists practicing in AMS already frequently engage with clinicians to improve the diagnostic process and have many skills needed for the implementation of diagnostic stewardship initiatives. As diagnostic stewardship becomes more broadly used, all infectious disease clinicians, including pharmacists, must collaborate to optimize patient care.

Results of a Randomized, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial of Nabpaclitaxel + Gemcitabine ± Olaratumab in Treatment-Naïve Participants with Metastatic Pancreatic Cancer.

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.

Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma.

The MYC proto-oncogenes (c-MYC, MYCN , MYCL ) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are MYCN -amplified. Genetically engineered mouse models (GEMMs) based on the MYCN transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC-driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas. In this study, we report two transgenic murine neuroendocrine models driven by conditional c-MYC induction in tyrosine hydroxylase (Th) and dopamine ß-hydroxylase (Dbh)-expressing cells. c-MYC induction in Th-expressing cells leads to a preponderance of Pdx1 + somatostatinomas, a type of pancreatic neuroendocrine tumor (PNET), resembling human somatostatinoma with highly expressed gene signatures of δ cells and potassium channels. In contrast, c-MYC induction in Dbh-expressing cells leads to onset of neuroblastomas, showing a better transforming capacity than MYCN in a comparable C57BL/6 genetic background. The c-MYC murine neuroblastoma tumors recapitulate the pathologic and genetic features of human neuroblastoma, express GD2, and respond to anti-GD2 immunotherapy. This model also responds to DFMO, an FDA-approved inhibitor targeting ODC1, which is a known MYC transcriptional target. Thus, establishing c-MYC-overexpressing GEMMs resulted in different but related tumor types depending on the targeted cell and provide useful tools for testing immunotherapies and targeted therapies for these diseases.

A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .

Dual-Modified Hyaluronic Acid for Tunable Double Cross-Linked Hydrogel Adhesives.

Conventional techniques for the closure of wounds, such as sutures and staples, have significant drawbacks that can negatively impact wound healing. Tissue adhesives have emerged as promising alternatives, but poor adhesion, low mechanical properties, and toxicity have hindered their widespread clinical adoption. In this work, a dual modified, aldehyde and methacrylate hyaluronic acid (HA) biopolymer (HA-MA-CHO) has been synthesized through a simplified route for use as a double cross-linked network (DCN) hydrogel (HA-MA-CHO-DCN) adhesive for the effective closure and sealing of wounds. HA-MA-CHO-DCN cross-links in two stages: initial cross-linking of the aldehyde functionality (CHO) of HA-MA-CHO using a disulfide-containing cross-linker, 3,3'-dithiobis (propionic hydrazide) (DTPH), leading to the formation of a self-healing injectable gel, followed by further cross-linking via ultraviolet (UV) initiated polymerization of the methacrylate (MA) functionality. This hydrogel adhesive shows a stable swelling behavior and remarkable versatility as the storage modulus (G') has shown to be highly tunable (103-105 Pa) for application to many different wound environments. The new HA-MA-CHO-DCN hydrogel showed excellent adhesive properties by surpassing the burst pressure and lap-shear strength for the widely used bovine serum albumin-glutaraldehyde (BSAG) glue while maintaining excellent cell viability.