Tag: Programmed Cell Death

Study reveals key protein’s role in balancing immune response to viral infections

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Researchers have revealed the regulatory mechanism of a specific protein that plays a key role in balancing the immune response triggered by viral infections in mammal cells. These findings could help drive the development of antiviral therapies and nucleic acid medicines to treat genetic disorders.

For cells to protect themselves from viral infections, a series of immune responses typically occur, including programmed cell death called apoptosis and interferon signaling. While apoptosis is a normal process, which occurs with or without the presence of viral molecules, following a cascade of steps to end with the death of a cell -; which might not sound advantageous to the host -; it can help prevent the reproduction of abnormal cells, including those infected by viruses, and eliminate them from the body. Interferons, on the other hand, are proteins produced by animal cells in response to a viral infection to protect the cell against viral attacks and prevent the virus from replicating. The regulatory mechanism of how cells maintain a balance between apoptosis and interferon response to efficiently suppress viral replication during infection, however, remained unclear.

In the current study, a team including researchers from the University of Tokyo focused on a specific protein, TRBP, which is also classified as a type of protein called an RNA silencing factor.

RNA is a nucleic acid, an organic compound found in living cells and viruses, which controls protein synthesis and the genetic makeup of many viruses. RNA synthesizes proteins through a process known as translation, by reading genetic sequences and translating them into instructions for the cells to create proteins, which are mostly responsible for the overall structure and function of the organism, whether it’s a plant or animal.

RNA silencing, also known as RNA interference, is a way that plants and invertebrate animals can protect themselves from viruses by cleaving viral RNA to repress viral replication.

This study provides a significant insight that clearly revealed the protein related to the RNA silencing mechanism, which is known to be an antiviral mechanism in a plant or invertebrate, is strongly related to antiviral response also in mammals by another mechanism.”

Tomoko Takahashi, co-author, visiting researcher at the University of Tokyo and assistant professor at Saitama University, Japan

Though it is widely understood that RNA silencing is a mechanism that operates under normal conditions to control gene expression (if the gene is “turned on” to provide instructions for the cell to assemble the specific protein it encodes), it’s still unclear how this process occurs under the stress of viral infection.

So the researchers looked at TRBP (an abbreviation for TAR RNA-binding protein), which has shown a significant role in RNA silencing during a viral infection.

This protein interacts with a virus sensor protein early on in the phases of infection in human cells. In the later stages of viral infection, proteins called caspases are activated, and this type of protein is chiefly responsible for triggering cell death.

“RNA silencing and interferon signaling were previously considered as independent pathways, but multiple reports, including ours, have demonstrated crosstalk between them,” said Kumiko Ui-Tei, another co-author and associate professor from the University of Tokyo (at the time of the study).

This functional conversion of TRBP triggered by viral infection is the basis of regulating interferon response and apoptosis, with TRBP irreversibly increasing the programmed cell death of infected cells, while reducing interferon signaling. TRBP works on the cell by inducing cell death, stopping the viral replication entirely, in contrast to the interferon response pathway, which just subdues viral replication instead of eliminating the infected cells.

“The ultimate goal is understanding the molecular mechanism underlying the antiviral defense system, orchestrated through the interplay between internal and external RNA pathways in human cells,” said Takahashi.

By gaining a deeper understanding of how defenses against viruses work on a molecular level, the researchers aim to drive the development of nucleic acid medicines. These medicines utilize targeting and inhibition approaches similar to the antiviral response of RNA silencing, and they hold promise of being increasingly useful in treating a wider range of patients afflicted with viral infections, genetic mutations and genetic defects.

This study was conducted in collaboration with Saitama University, Chiba University, Kyoto University and Maebashi Institute of Technology in Japan.

Source:

Journal reference:

Shibata, K., et al. (2024) Caspase-mediated processing of TRBP regulates apoptosis during viral infection. Nucleic Acids Research. doi.org/10.1093/nar/gkae246.

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April 19, 2024
Study reveals key mechanism of PD-1 function

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Insights into the workings of an immune cell surface receptor, called PD-1, reveal how treatments that restrict its action can potentially be strengthened to improve their anticancer effect, a new study shows. The same findings also support experimental treatment strategies for autoimmune diseases, in which the immune system attacks the body, because stimulating the action of PD-1, as opposed to restricting it, can potentially block an overactive immune response.

Led by researchers at NYU Langone Health’s Perlmutter Cancer Center and the University of Oxford, the study is publishing in the journal Science Immunology online March 8.

The study results revolve around the body’s immune system, which is primed to attack virally infected and cancerous cells while leaving normal cells alone. To spare normal cells from immune attack, the system uses “checkpoints,” sensors on the surface of immune cells, including T cells, which turn them off or dampen activation when they receive the right signal. The immune system recognizes tumors as abnormal, but cancer cells can hijack checkpoints to turn off immune responses.

Among the most important checkpoints is a protein called programmed cell death receptor 1 (PD-1), which is shut down by a relatively new drug class called checkpoint inhibitors to make tumors “visible” again to immune attack. Such drugs are at least somewhat effective in a third of patients with a variety of cancers, say the study authors, but the field is urgently seeking ways to improve their performance and scope.

At the same time, PD-1 signaling is slowed in autoimmune diseases like rheumatoid arthritis, lupus, and type 1 diabetes, such that the action of unchecked immune cells creates inflammation that can damage tissues. Agonists, drugs that stimulate PD-1, are now showing promise in clinical trials.

Many immune checkpoints are receptors on the surface of T cells that act to translate docking information from the outside of the cell to the signaling portion of the receptor inside the cell. Connecting the outside-of-the-cell portion of PD-1 with the inside portion is the transmembrane segment. Many immune receptors function in pairs called dimers, but to date, PD-1 has been thought to function alone, not in the dimer form.

Study results showed that PD-1 forms a dimer through interactions of its transmembrane segment. Researchers say this finding is in sharp contrast to other immune receptors, which typically form dimers through the segment of the receptor that is outside the cell.

Further immune cell testing in mice showed that encouraging PD-1 to form dimers, specifically in the transmembrane domain but not in its outer or inner regions, increased its ability to suppress T cell activity, while decreasing transmembrane dimerization lowered PD-1’s ability to inhibit immune cell activity.

Our study reveals that the PD-1 receptor functions optimally as dimers driven by interactions within the transmembrane domain on the surface of T cells, contrary to the dogma that PD-1 is a monomer.”

Elliot Philips, MD, PhD, Study Lead Investigator and Physician-Scientist, NYU Grossman School of Medicine

Elliot Philips is an internal medicine resident at NYU Grossman School of Medicine and Perlmutter Cancer Center. Philips is also an alumnus of the Vilcek Institute of Biomedical Sciences at NYU.

“Our findings offer new insights into the molecular workings of the PD-1 immune cell protein that have proven pivotal to the development of the current generation of anticancer immunotherapies, and which are proving essential in the design and developing of the next generation of immunotherapies for autoimmune diseases,” said study co-senior investigator and cancer immunologist Jun Wang, PhD. Wang is an assistant professor in the Department of Pathology at NYU Grossman and Perlmutter.

“Our goal is to use our new knowledge of the functioning of PD-1 to determine if weakening its dimerization, or pairing, helps make anticancer immunotherapies more effective, and just as importantly, to see if strengthening its dimerization helps in the design of agonist drugs that quiet overactive T cells, tamping down the inflammation seen in autoimmune diseases,” said study co-senior investigator and structural biologist Xiang-Peng Kong, PhD. “Presently, research efforts have focused on strengthening PD-1 interactions with its ligands, or signaling molecules, involved with inhibiting T cell action.

“Our new study suggests that efforts to design better drugs should focus on increasing or decreasing PD-1’s dimerization to manipulate T cell function,” said Kong, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman and Perlmutter.

Among the study’s other findings was that a single change in the amino acid structure of the transmembrane segment can act to either enhance or diminish the inhibitory function of PD-1 in immune responses. The team plans further investigations of PD-1 inhibitors and agonists to see if they can tailor what they say are more effective, “rationally designed” therapies for both cancer and autoimmune disorders.

Funding support for the new study was provided by National Institutes of Health grants R01AI125640, R37CA273333 T32AR069515, and T32GM007308. Additional funding support was provided by NYU Grossman School of Medicine, Kennedy Trust for Rheumatology Research grant 100262Z/12/Z; Research Council of Norway grant 275466, in conjunction with Marie Sklodowska-Curie Actions; Wellcome Trust grant 108869/Z/15/Z; the Melanoma Research Alliance; and a pilot award from the NYU Colton Center for autoimmunity. Wang has been a paid consultant to RootPath Genomics, Bristol Myers Squibb, and Hanmi Pharmaceutical and is a founder, equity holder, and consultant to Remunix. These interests and relationships are being managed in accordance with the policies of NYU Langone Health.

Besides Philips, Wang, and Kong, other NYU Langone researchers involved in this study are colead investigator Jia Liu, and coinvestigators Charles Ng, Ian Ahearn, Ruimin Pan, Christina Luo, Alexander Leithner, Zhihua Qin, and Dan Littman, who is also a Howard Hughes Medical Institute investigator. Other study coinvestigators include Audun Kvalvaag, at Oslo University, Norway; Alexander Morch and co-senior investigator Michael Dustin, at the University of Oxford, United Kingdom; Anna Tocheva, at the Icahn School of Medicine at Mount Sinai in New York; Hong Liang and Yong Zhou, at the University of Texas in Houston; Antonio Garcia-Espana, at the University of Rovira i Virgili in Tarragona, Spain; and Adam Mor, at Columbia University in New York.

Source:

Journal reference:

Philips, E. A., et al. (2024) Transmembrane domain–driven PD-1 dimers mediate T cell inhibition. Science Immunology. doi.org/10.1126/sciimmunol.ade6256.

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March 9, 2024
Gut bacteria strains could be the key to predicting cancer treatment success

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In a recent study published in Nature Medicine, researchers investigated the composition of the gut microbiota as a predictive marker for immune checkpoint blockade (ICB) responsiveness and toxicity.

ICB drugs that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have transformed cancer therapy. Combination ICB has synergistic anticancer efficacy but is associated with variable responses and adverse immune-related side effects. Current tumor-agnostic biomarkers for PD-1 inhibition have limitations and depend on accessible tumor tissue. Gut microbiota composition may impact clinical response to ICB; however, identifying microbiome-based biomarkers for ICB response is difficult due to strain-specific measurement.

Study: A gut microbial signature for combination immune checkpoint blockade across cancer types. Image Credit: CI Photos / Shutterstock

About the study

In the present study, researchers analyzed deep shotgun metagenomic sequences from stool samples of the phase 2 CA209-538 trial cohort of rare cancer patients treated with ICB drugs such as nivolumab and ipilimumab. They investigated whether a patient’s gut microbiota composition may predict ICB responsiveness and toxicity.

The trial included 120 individuals with histologically advanced stage solid-organ tumors from five hospital networks in Australia. The tumor histologies were diverse and categorized into three predetermined groups: upper gastrointestinal and biliary tumors (UGB), rare gynecological cancers (GYN), and neuroendocrine neoplasms (NEN). The majority of patients had previously undergone systemic anticancer treatments, and all participants in the trial were treated with a combination of ipilimumab and nivolumab for ≤4.0 doses (induction) and nivolumab maintenance therapy for ≤2.0 years or till progressive disease (PD) development.

The researchers predicted that distinct strains may predict combination ICB effectiveness in the sample. They used objective response versus progression (RvsP), defined as a RECIST best overall response (BOR) of partial response (PR) or complete response (CR) vs. cPD or PD, as the primary endpoint. They eliminated individuals with a BOR of stable disease (SD) since it is ambiguous in a pan-cancer sample. The secondary endpoint was to create ‘tumor-agnostic’ indicators for combination ICB responses by exploiting CA209-538’s trial design. Most participants provided pretreatment fecal samples, and there were no significant clinical differences between microbiome-evaluable individuals and those unsampled.

Researchers sequenced 106 baseline stool samples using deep shotgun metagenomics to better understand patients’ gut microbial compositions. They adopted the genome-resolved strategy, using metagenome-assembled genomes (MAGs) and applicable Genome Taxonomy Database (GTDB) species reference genomes (SRGs) to create a study-specific microbial strain database for reference. Based on the patients’ BOR and intersample beta diversity, the researchers used the Aitchison distance to determine if there were significant compositional variations.

The researchers used PFS12 and supervised machine learning algorithms to measure the performance of 15 clinical and microbiological parameters. They concentrated on strain-RvsP classifiers due to their superior performance and incremental advantage over ordinary clinical variables. They compared forecasts to patient BOR results and found strain abundances to be significant factors. They also analyzed the genomes of the top 22 strains to improve their understanding of their functional potential and performance in combination with ICB and anti-PD-1 monotherapy cohorts. Strain-RvsP RF classifiers were trained and evaluated across all strain abundances and cohort combinations.

Results

The findings indicated that strain-specific microbe abundances can improve machine-learning estimations of immune checkpoint blockade response and one-year progression-free survival compared to models based on species-rank quantifications or pretreatment clinical variables. Through the meta-analytical research of intestinal metagenomes obtained from six studies (364 individuals, validation cohort), the team found cross-country and cross-cancer validity of microbial strain-response characteristics using concordant ICB training and testing regimens (drugs targeting PD-1 or those combined with drugs targeting CTLA-4).

The results show that strain-resolved microbial abundances enhance machine-learning predictions of ICB response and 12-month progression-free survival compared to models based on species-rank quantifications or pretreatment clinical variables. The overall (OS) and progression-free survival (PFS) rates were more stable among histological cohorts. The team observed a significant positive relationship between albumin and BOR, especially in individuals with fast clinical development.

The BOR metadata characteristic explained the highest microbiological variation among the 23 pretreatment clinical and technical sample information examined. However, patient progression-free survival or overall survival at one year showed minimal microbial variation. Strain-responsiveness signatures were consistent across cancers, although clinical variables alone were insufficient predictors of RvsP. The research location and deoxyribonucleic acid (DNA) extraction kit were the most significant causes of microbial variation throughout the meta-cohort.

The study suggests that future gut microbiome diagnosis must depend on treatment regimens rather than cancer type. Assessing a patient’s baseline gut microbiota composition may help predict ICB response and toxicity. In a phase 2 study of Australian patients with uncommon malignancies, researchers utilized strain-resolved metagenomic classification to identify 22 gut microbial strains linked to ipilimumab and nivolumab responses. The data support strain resolution in gut microbial ICB indicator development, generalizability across cancer types and geographic regions, and regimen disaggregation in future studies.

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March 7, 2024
Antibody combination shows safety and anti-tumor activity in advanced cancer patients

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In an early phase clinical trial, a combination of antibody-based medications targeting the immune system generated promising safety data and anti-tumor activity in individuals with various types of advanced cancer. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

Both medications tested in the trial support immune responses against tumor cells. CS1002 increases the activation and proliferation of T immune cells by binding to a T cell receptor called CTLA-4. CS1003, also called nofazinlimab, blocks the programmed cell death protein 1 that is expressed on various types of immune cells and plays a role in suppressing the immune system.

In this first-in-human multicenter, open-label study conducted from April 26, 2018 to January 18, 2022 at 9 study sites in Australia and China, phase Ia involved monotherapy dose-escalation (Part 1), which was followed by phase Ib combination therapy dose escalation (Part 2) and expansion (Part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg once every 3 weeks, or 3 mg/kg once every 9 weeks) were evaluated with 200 mg CS1003 once every 3 weeks.

Parts 1, 2, and 3 of the trial included 13, 18, and 61 patients, respectively, who had advanced/metastatic solid, relapsed, or refractory tumors. During treatment, investigators did not observe any dose-limiting toxicities or a maximum tolerated dose. Treatment-related side effects such as diarrhea, fatigue, and rash were reported in 30.8%, 83.3%, and 75.0% of patients in Parts 1, 2, and 3, respectively. Serious side effects such as intestinal inflammation and severe skin reactions were experienced by 15.4%, 50.0%, and 18.3% of patients in each part.

Of 61 patients evaluable for treatment efficacy, 23 (37.7%) with different types of tumors experienced a positive response. Higher response rates occurred with conventional and high-dose CS1002 regimens (1 mg/kg once every 3 weeks or 3 mg/kg once every 9 weeks) compared with low-dose CS1002 (0.3 mg/kg once every 3 weeks) in certain cancers such as melanoma and skin cancer.

“CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising anti-tumor activities across CS1002 dose levels when combined with CS1003,” the investigators wrote. “This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.“

Source:

Journal reference:

Bishnoi, S., et al. (2024) Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study. Cancer. doi.org/10.1002/cncr.35226.

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February 26, 2024
Advanced melanoma survival rates improve significantly from 2013 to 2019, Dutch study finds

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In a recent study published in EClinicalMedicine, a group of researchers assessed the change in overall survival (OS) among advanced melanoma patients diagnosed between 2013 and 2021.

Study: Improving survival in advanced melanoma patients: a trend analysis from 2013 to 2021. Image Credit: Africa Studio/Shutterstock.com

Background

The outlook for advanced melanoma, encompassing unresolvable stage III and IV cases, has markedly improved due to the advent of novel treatments.

Starting with the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) blocking antibody ipilimumab in 2012, the treatment landscape expanded to include B-Raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors for patients with BRAF-mutant melanoma in 2012, anti-Programmed Cell Death (PD)-1 antibodies in 2015, and combinations of BRAF inhibitors with Mitogen-Activated Protein Kinase (MEK) inhibitors and ipilimumab with nivolumab in 2016.

Recent advancements also introduced therapies such as Lymphocyte-Activation Gene 3 (LAG-3) antibodies and Tumor-Infiltrating Lymphocyte (TIL) therapy. In the Netherlands, survival rates have risen following these innovations, even outside clinical trials.

Further research is needed to understand the factors driving the recent decline in survival rates and to develop strategies to improve outcomes for advanced melanoma patients, particularly in the coronavirus disease 2019 (COVID-19) pandemic and evolving treatment modalities.

About the study

The data for the present study was sourced from the Dutch Melanoma Treatment Registry (DMTR). They involved patients aged 18 and over diagnosed with advanced melanoma from 2013 to 2021, specifically focusing on those who received systemic treatment.

These patients were categorized based on the year their melanoma was diagnosed as unresectable.

Those who progressed to unresectable disease following neoadjuvant or adjuvant treatments were included from the point they commenced treatment for their unresectable condition. Exclusions were made for patients with uveal or mucosal melanoma.

Patient demographics and tumor characteristics at the point of advanced disease diagnosis – including age, gender, performance status, lactate dehydrogenase levels (LDH) levels, melanoma location and type, thickness, ulceration presence, liver and brain metastases, number of metastatic organ sites, American Joint Committee on Cancer (AJCC) 8th edition staging, and mutation status were carefully recorded. The study also differentiated between synchronous and metachronous presentations of melanoma.

Statistical analysis was conducted using various methods to compare baseline characteristics and to estimate median survival times and the impact of the year of diagnosis on overall survival.

This involved descriptive statistics, Pearson’s chi-squared, and t-tests for categorical and continuous variables, respectively. Survival analysis was performed with the Kaplan-Meier method, and the Cox proportional hazards model was applied for multivariable analysis, considering several factors identified from previous research.

Statistical computations were performed using R software and several packages for data manipulation and analysis, ensuring a comprehensive and rigorous statistical examination of the collected data.

Study results

Between 2013 and 2021, the DMTR recorded 7,928 patients with advanced melanoma. After excluding cases of uveal and mucosal melanoma, 7,317 patients were included in the analysis.

Many of these patients received systemic treatment, increasing from 74% in 2013 to 86% in 2020 and slightly decreasing to 83% in 2021.

Out of those treated, 6,260 patients were included after further exclusions for uveal and mucosal melanoma. Among these, 428 had received neoadjuvant or adjuvant treatment before their systemic treatment for advanced melanoma.

The study observed a median follow-up of 50.9 months, with the longest follow-up for the 2013 cohort at 106.0 months and the shortest for the 2021 cohort at 14.1 months.

The median age of patients diagnosed with advanced melanoma increased over the years, and there was a noticeable rise in the number of patients with poor performance status and brain metastases. Interestingly, the prevalence of synchronous metastatic disease also increased, particularly in 2020 and 2021.

Treatment modalities evolved from BRAF inhibitors and ipilimumab monotherapy to BRAF/MEK inhibitors, anti-PD-1 antibodies, and combination therapies. The study also noted changes in the duration of these treatments over time.

The median OS for systemically treated advanced melanoma patients improved from 11.2 months in 2013 to 32.0 months in 2019.

However, a decline was observed in patients diagnosed in 2020 and 2021, with median OS dropping to 26.6 and 24.0 months, respectively, although these decreases were not statistically significant.

This trend was mirrored in the melanoma-specific survival (MSS) data, with improvements seen until 2019, followed by a decrease for the cohorts of 2020 and 2021.

Furthermore, the study found that neoadjuvant and adjuvant treatments did not significantly affect survival outcomes for advanced melanoma. Patients with synchronous metastases had shorter survival than those with metachronous metastases.

Despite treatments improving survival post-2013, a concerning trend of increased mortality risk was noted for diagnoses in 2020 and 2021, underscoring the urgency for ongoing research and treatment adaptation.

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February 14, 2024
Hydrogel with built-in antibiofilm and antioxidative functions promotes faster healing of infected chronic wounds

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Diabetic wounds often become chronically infected and are notoriously difficult to treat. Two primary reasons for this include the formation of a bacterial biofilm and high levels of oxidative stress. A novel hydrogel dressing was developed recently to combat both these undesirable characteristics and tested for its effects on diabetic-infected wound healing. The report appeared in Nature Communications.

Study: Hydrogel dressings with intrinsic antibiofilm and antioxidative dual functionalities accelerate infected diabetic wound healing. Image Credit: New Africa/Shutterstock.com

Background

Wound healing is recognized to have four stages, namely, coagulation, inflammation, proliferation, and maturation. When this doesn’t happen, chronic wounds result. Most occur due to prolonged inflammation triggered by competing pro- and anti-inflammatory signals leading to loss of redox homeostasis.

Chronic inflammation attracts leukocytes that secrete reactive oxygen species (ROS), a defense against microbial invasion. However, these ROS also antagonize wound healing by damaging living tissues and cells at various levels and promoting breakdown and further inflammation.

In the worst cases, cells die within and around the wound site by apoptosis and other modes of programmed cell death because of excessively high ROS levels. Neighboring cells react to this and eventually die themselves, accounting for the severe necrosis, or tissue death, common to such wounds. This means that tissue debridement or even amputations, at times, becomes necessary to treat these wounds.

Biofilm formation by microbes is another complication that gives rise to chronic wounds, preventing topical antioxidants from acting on the wound surface. Biofilms use up nutrients from the wound bed and secrete extracellular polymeric substances (EPS) that form a protective barrier against immune cells, antibiotics, and other antimicrobials. Moreover, they remain stable on the wound surface until medically removed.

Biofilm microbes are, in fact, the primary species found in chronic wounds and are resistant to treatment in many cases. Most commonly, these are methicillin-resistant Staphylococcus aureus (MRSA) or carbapenem-resistant Pseudomonas aeruginosa (CRPA).

Chronic wounds cost the economy over USD 50 billion in just the USA, in just one year. And this is only expected to increase as the population grows around the world. Diabetic wounds are among the most common types of chronic wounds and have, unfortunately, as high a risk of death as cancer, at about 31%.

The effectiveness of ordinary wound dressings in chronic wounds is small. Dressings designed for chronic wounds have so far not been developed as stand-alone treatments. At present, specialized chronic wound dressings require the additional use of photothermal irradiation or release and leave significant amounts of antibiotics or metal ions in the wound.

The current study was motivated by the need for improved chronic wound dressings that would be adequate by themselves, would not contaminate the wound, and would not produce unwanted discharge and moist wound matter.

The researchers used a hydrogel, PPN, formed by crosslinked polyethylene glycol (PEG) hydrogel tethered with highly potent antibacterial cationic polymer, polyimidazolium (PIM), and the antioxidant N-acetylcysteine (NAC). The cationic hydrogel kills bacteria by absorbing them into its pore spaces and then contact killing by the pore walls.

PPN was designed to have dual functionality, opposing both biofilm formation and oxidative stress in the wound bed. Both properties would act together in synergy to promote the healing of infected diabetic wounds.

Very little of this hydrogel leaches into the wound, and it contains neither antibiotic nor metal compounds, ensuring the wound is uncontaminated by any of these once the dressing is taken off.

What did the study show?

PPN showed high antibacterial efficacy in vitro. The hydrogel formulations swelled up, absorbing 10-12 times their original weight of water within an hour. In two days, when tested in infected wounds on murine models, the hydrogels became dirty yellow, probably because of the absorption of fluid and dead bacteria in the wound. They remained structurally stable, however, indicating that they do not break down in the presence of infected wounds.

The researchers tested these hydrogels on a human skin model that was grown in a 3D structure. This demonstrated improved keratinocyte differentiation in the presence of NAC. In addition, it speeded up re-epithelialization and, thus, wound closure. Notably, silver dressings have been shown to retard keratinocyte proliferation in chronic wounds.

Subsequently, they applied the dual-functionality hydrogel on infected wounds in diabetic rats, which closely resembled diabetic wounds in humans. The wounds were coated with a biofilm containing either MRSA or CRPA.

The hydrogels showed excellent biocompatibility compared to silver dressings in current use. The infected wounds treated with the hydrogel showed rapid healing compared to those in control animals. Bacterial counts fell rapidly and steeply over the first three days and remained low over the next two weeks.

In contrast, bacterial reduction was lower for both silver dressings and control dressings. The wounds were smaller and sloughing minimal in PPN-treated wounds compared to silver or control dressings or no treatment. In fact, untreated wounds showed biofilm formation and pus discharge with sloughing wounds, with evidence of reinfection.

Wound healing factors were also found at higher levels in PPN-treated wounds than in untreated or control-treated wounds. More mature collagen was found in the PPN-treated wound, indicating better regeneration of skin structure. Both components of PPN were found to contribute to the improved results compared to only one.

The hydrogel can be formulated in different ways for application to the healing of superficial or deep wounds. Its advantages include the absence of wound contamination and the fact that it does not require the use of photothermal irradiation or other healing modalities.

What are the implications?

PPN first removes bacteria from the wound site, allowing the number of inflammatory cells to drop. ROS levels are reduced by the NAC component, which allows them to diffuse into the hydrogel, providing an immune boost while relieving oxidative stress. Also, it encourages the release of wound-healing factors.

Finally, the NAC stimulates keratinocyte differentiation and the restoration of a normal epithelial covering over the wound. All these promote wound healing.

This PPN dressing is more potently antibacterial than silver dressing, with activity against MRSA and CRPA. It also does not cause further inflammation and accelerates wound healing. The feasibility of multiple formats for meeting different needs and its possible extension to other biomedical needs make this hydrogel a promising alternative for the treatment of chronic infected diabetic wounds.

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February 5, 2024