MedComm – Biomaterials and Applications最新文献

A recent article published in Cell¹ reported that the multiplexed effector guide arrays (MEGA) based on the CRISPR-Cas13d system can contribute to improving chimeric antigen receptor (CAR) T cell exhaustion by massively multiplexed, quantitative, and reversible perturbation of the transcriptome in primary human T cells. This study reminds us that Cas9 may be no longer the dominating force or the only choice in the gene-editing and precision therapy field, and other contenders, including Cas13d, Cas12a as well as numerous unknown systems will come into the fray in not long future.

The successful application of CAR T therapy, as everyone knows, could tremendously benefit tumor-targeted therapy but is plagued by the following challenges, such as T cell exhaustion, cytotoxicity, and off-target effects. To address these issues, Tieu and colleagues developed a MEGA platform by harnessing the Cas13d system that is characterized by the RNA-guide RNA endonuclease activity without PAM sequence recognition, the ability to process poly-crRNA guide arrays to facilitate efficient simultaneous targeting of multiple RNA transcripts in single cells, and the smaller molecular weight compare with Cas9 (Figure 1). First, the authors have succeeded in optimizing MEGA HA-28ζ CAR T cells that robustly suppress the exhaustion marker (LAG3, PD-1, and TIM3) upregulation on transcriptional and surface protein levels and have positively affected the tumor-killing activity of chimeric T cells. Moreover, the MEGA expression and effective processing did not induce interferon (IFN) pathway activation, which is a critical signal for tumor surface recognition of CAR T cells and may be one reason of tumor-killing activity enhancement in chimeric T cells.² More importantly, single-vector bicistronic configurations show that this system has low viral titers, which may benefit from the crRNA-guided cleavage of lentiviral RNA of Cas13d, whereas non-induction of IFN signaling is also extremely important to CAR T cell-mediated cytotoxicity elimination.²

Indeed, previous studies have also provided evidence for CRISPR-Cas9 on pathogenic RNA-targeted elimination and IFN signal inhibition via its powerful gene silencing ability.^{2, 3} Nevertheless, one typical advantage of the MEGA platform is that it can process a long array of nearly 10 targeted genes simultaneously dispensing with independent gRNA guiding, although the knockdown efficiency is uneven when without prior optimization of spacer sequence or position. This has phased significance for data validation of CRISPR-based whole-genome screening or conventional RNA-seq analysis in biological research.^1-3 MEGA provides a powerful example in experimental co-validation of multiple candidate genes in the purinergic signaling and the PI3K/Akt pathway, and its multiplexing capability allows for expendin

This manuscript aims to three-dimensional bioprint and evaluate new polymer composite scaffolds based on synthesized poly(ethylene glycol) dimethacrylate (PEGDMA) as well as methyl cellulose and gelatin. The PEGDMA was synthesized by a simple microwave-assisted method using three distinct molecular weights (MWs) of poly(ethylene glycol) (PEG), 3, 6, and 12 kDa, and methacrylic anhydride. The percent functionalization of the PEGDMA was analyzed using the nuclear magnetic resonance spectrum, and the theoretical calculations indicated that over 50% of methacrylation was achieved in all samples, with the PEGDMA synthesized from 6 kDa PEG surpassing 66% methacrylation. These three PEGDMA-based bioinks were investigated for their suitability for bioprinting scaffolds. It was observed that lower MW PEGDMA resulted in a higher degree of crosslinking, leading to more stable composite scaffolds. However, higher crosslinking degree did not support long-term cell viability when encapsulated with cells. Higher MW PEGDMA showed higher cell viability over time though overall stability was lower. Synthesized PEGDMA with 6 kDa PEG showed both stability and long-term cell viability after postprinting. Over 80% of cell viability was maintained for a 7-day study period, showing potential use in tissue engineering applications as a cell delivery vehicle.

The human skin and mucosal systems build a continuous exterior barrier that encloses the entire body. This natural barrier protects the body by preventing the free entry of a majority of foreign substances, whereas nutrients and selected substances can be transported via either passive or active mechanisms. Unfortunately, the presence of biobarriers also stymies the absorption of therapeutic agents. Breaking through these absorption barriers is one of the leading challenges in modern drug delivery.

The most direct and efficient approach is to breach the barrier by invasive techniques such as injection, microneedle injection, high-pressure powder injection, ionophoresis, and electroporation. However, owing to the well-known safety concerns of barrier damage, noninvasive alternatives with less optimal efficiency are always preferred. The current key issue with noninvasive permeation enhancement is improving the permeation efficiency while preserving the physiological functions of the protective barriers.

Currently, there are a variety of permeation enhancers that act via different mechanisms, including but not limited to small chemicals, polymers, peptide chaperones, and nanovehicles. Among them, chemical permeation enhancers (CPEs) are simple in structure and stable in terms of their physicochemical properties and are therefore easily applicable for different transdermal or trans-mucosal drug delivery purposes. Traditional CPEs such as ethanol, dimethyl sulfoxide, laurocapram, cholates, salcaprozate sodium (SNAC), essential oils, chitosans, etc., function through intricately orchestrated mechanisms of extracting and fluidizing biomembranes or opening intercellular tight junctions. Recent developments in enhancing the oral bioavailability of proteins and peptides by SNAC have highlighted the benefits that CPEs can offer. Nonetheless, debilitating biobarriers by CPEs may cause simultaneous invasion of toxins and pathogens and pose a safety risk. In recent decades, there has been continuous exploration for more potent and safer CPEs. However, dismally, little progress has been made in discovering new types of CPEs. Despite limited success in clinical applications, the development lags far behind the demand for innovative CPEs. Fortunately, the most recent research on transdermal and transmucosal drug delivery has shed light on ionic liquids (ILs) as a unique kind of novel CPE.

ILs are defined as “liquid salts” formed by organic cations and anions through ionic interactions. Unlike solid salts formed by neutralization reactions between a pair of strong acids and bases, one of the cation/anion pairs should be a weak acid or base. Therefore, the interactions in ILs are weaker than the ionic bonds formed in strong acid/base salts, presenting ILs as “liquid salts” with a melting point less than 100°C or ideally at physiological temperatures to address the unmet needs in biomedicines, especially in drug delivery. Notably, there are not

Bone defect is a common clinical disease. Due to the uncertainty of trauma or infection areas, customized size features are often required for bone substitutes. By inspiration of the natural bone structure, this study designs porous scaffolds with a biomimetic design perspective by using different inner and outer pore units. The outer pore units adopt body-centered cubic (BCC) structure to simulate the weight-bearing function of human cortical bone, while inner pore units using I-Wrapped Package structure, a kind of three periods minimum surface, to obtain a good permeability and simulates the inner layer of cancellous bone. To further regulate the overall modulus of the scaffold within the range of natural bone modulus in the human body, the scaffold was designed to axial gradient structure. Compression experiments were conducted, and the results indicated that when the volume fraction linearly increased from 20% to 50%, the Young's modulus was close to the cortical bone modulus in the human body. In vitro cell experiments further proved that osteoblasts have good cellular activity and spreading morphology on the surface of this scaffold. The customized 3D-printed heterogeneous porous titanium scaffold has great application potential in bone tissue engineering.

Brain-computer interfaces (BCIs), an advanced technology that is designed to record and decode brain activity, may transmit information communication between the brain and external devices, such as computers, wheelchairs, and robotic arms¹ (Figure 1). Elon Musk recently tweeted: his Neuralink company revolutionizes BCI technology, announcing a clinical trial of the implantation of a “brain-reading” device into a human, which has enlightened the field of neurotechnology. This trial represents a milestone in the long journey to improve BCIs, a scientific area aimed to restore functionality to those with severe paralysis and expanding the boundaries of human-machine interaction.

This innovative technology might transform the lives of individuals with motor disabilities, enabling them to control a computer, robotic arm, wheelchair, or other device by thinking about it and interact with the world through these devices. Neuralink's device is not the only BCI technology under development. Other companies and research groups, like BCI Pioneers Coalition, are also working on similar technologies, and some of them have earlier entered to human trials. If proven its effectivity and safety, Nerualink's device may significantly change the field (Figure 1).

However, announcing the trial has also raised a slew of concerns. First, the lack of detailed information about the trial has frustrated some neuroscientists and engineers. While we heard information about the trial's commencement that may be found in a proper channel. The main source of public information lacks crucial details, such as the location of implantations and exact outcomes, which may complicate the trial and cause anxiety in the public.

In addition, there is no registration about this trial at ClinicalTrials.gov, raising ethical concerns. Registration at this online repository is typically required by trial institutes to ensure transparency and adherence to ethical principles designed to protect participants in clinical trials. If bypassed these important checks and balances, the trial may compromise the safety and well-being of the participants.

Another dispute with the Neuralink's trial is that its pre-existing animal experiments caused too many animal deaths. According to the Reuters in December 2022, Neuralink's trials resulted in the deaths of more than 1500 animals, and an employee wrote internally to point out that the company's rush to meet the schedule caused many employees to be nervous, thus increasing the non-essential suffering and death of the animals under test. Miguel Nicolelis, professor of neuroscience at Duke University School of Medicine in the United States (father of brain computer interface), has previously said that invasive brain computer interfaces are for scientific research, and are not the best choice for patients, and the implantation method should be limited to very serious cases.

Despite these potential adve

Amid the escalating prevalence of eye diseases and the intricate nature of the eye as a crucial target organ for drug delivery, researchers face significant challenges in developing delivery systems tailored specifically for ocular complications. Addressing the gaps in the current conventional ocular drug delivery system (ODDS) is crucial and this can be achieved by incorporating polymers while designing newer ODDS. This review aims to offer a concise overview of the diverse polymers utilized in the development of ODDS, designed to address various eye conditions and disorders, enhance treatment outcomes, and ensure patient adherence. Introducing the anatomy of the eye and different ocular routes of administration, alongside the barriers encountered, this review presents polymer-based ODDS, renowned for their unique properties facilitating the engineering of specialized devices for enhanced drug delivery. Further discussions delve into the applications of polymers in ophthalmology. Emphasis is placed on emerging polymer-based technologies available in the market for treating ocular diseases, underscoring their potential for revolutionizing ocular healthcare. The review also addresses challenges in translating these advancements into clinical practice, while highlighting the versatility of polymers in treating diverse eye diseases and disorders through customizable properties and sustained drug delivery.

In tissue engineering, the pivotal role of scaffolds is underscored, serving as key elements to emulate the native extracellular matrix. These scaffolds must provide structural integrity and support and supply electrical, mechanical, and chemical cues for cell and tissue growth. Notably, electrical conductivity plays a crucial role when dealing with tissues like bone, spinal, neural, and cardiac tissues. However, the typical materials used as tissue engineering scaffolds are predominantly polymers, which generally characteristically feature poor electrical conductivity. Therefore, it is often necessary to incorporate conductive materials into the polymeric matrix to yield electrically conductive scaffolds and further enable electrical stimulation. Among different conductive materials, carbon nanomaterials have attracted significant attention in developing conductive tissue engineering scaffolds, demonstrating excellent biocompatibility and bioactivity in both in vitro and in vivo settings. This article aims to comprehensively review the current landscape of carbon-based conductive scaffolds, with a specific focus on their role in advancing tissue engineering for the regeneration and maturation of functional tissues, emphasizing the application of electrical stimulation. This review highlights the versatility of carbon-based conductive scaffolds and addresses existing challenges and prospects, shedding light on the trajectory of innovative conductive scaffold development in tissue engineering.

The mRNA formulations with lipid nanoparticle (LNP) delivery represent a transformative biotechnology that has demonstrated boundless potential during the global COVID-19 pandemic. Despite generally tolerable after used in billions of vaccine recipients, some toxicity cases have been reported, which presents challenges due to widespread application of mRNA vaccines. In our view, strategies to mitigate the toxicity risks associated with mRNA drugs, are crucial for ensuring the safety and efficacy of these therapies. The comprehensive introduction of LNP structural components, production methods, administration routes, and the proteins produced from mRNA formulations provides valuable insights into addressing potential toxicity concerns. However, it is important to acknowledge that throughout the entire mRNA therapeutic process, there are inherent toxicity risks that need to be carefully managed. These risks could pose a considerable challenge for the broad adoption of mRNA vaccines and other mRNA-based therapies (Figure 1).

The primary objective of this perspective is to explore strategies for reducing the toxicity risks associated with mRNA drugs and vaccines, including improving delivery systems, adjusting dosage and timing, and employing auxiliary molecules. To address these issues, in-depth research on the potential toxicity of mRNA vaccines are necessary, including a more comprehensive evaluation of their long-term effects in animal models and humans.

Furthermore, utilizing induced pluripotent stem cell, organoids, spheroids, and microfluidic technologies can enhance the physiological relevance and data diversity of in vitro studies. The authors emphasize new trends in in vitro modeling, including high-throughput models and machine learning algorithms. They highlight the potential of organ-on-chip technology, which recreates 3D tissues mirroring specific organs' phenotype, functionality, and transcriptomic profiles. These techniques allow the emulation of pathological physiological conditions in vitro and enable the tracking of molecular pathways associated with drug toxicity.

We emphasize the importance of developing physiologically relevant in vitro models to mitigate risks in the preclinical development process. The ethical considerations, limited availability of animals, and FDA's reliance on in vitro data all raise concerns regarding the safety of mRNA vaccines, as well as the accuracy of physiologically relevant in vitro models. Strengthening safety assessment is crucial, necessitating comprehensive studies, monitoring of diverse populations, and establishment of robust surveillance systems to investigate adverse events following mRNA vaccination.

Frontier areas in mRNA drug delivery technology are yet to be explored, presenting new possibilities for mitigating the toxicity risks linked to mRNA drugs and vaccines. Microneedles responsive to mechanical, temperature, electrical, optical, magnetic, pH, and variou

Wound healing and prevention of bacterial infections are critical aspects of modern medical care. In this work, antibacterial films were produced by creating composites of polycaprolactone with inorganic peroxides. Calcium, magnesium, and zinc peroxide were incorporated in a biocompatible polymeric film. Iron oxide, sodium bicarbonate, and calcium phosphate were added to reduce hydrogen peroxide and to maintain pH in a less alkaline range, allowing for optimization of the material's antibacterial efficacy while minimizing cytotoxicity toward human fibroblasts. Experiments with common wound pathogens, Staphylococcus aureus and Pseudomonas aerugonisa, confirmed significant and prolonged antibacterial effects of peroxide-doped films. Findings showed that the addition of CaO₂ and MgO₂ within the film increased cytotoxicity toward human fibroblasts after 48 h (30%–40% decrease compared to control), whereas ZnO₂-based films exhibited a minimal cytotoxicity consistently maintaining over 70% cell viability throughout the course of the experiment. We examined the materials’ sustained release of reactive oxygen species and oxygen, and pH variation correlated with antibacterial activity. Given the unique combination of antibacterial efficacy and mammalian biocompatibility, these peroxides have value as components to sustain hydrogen peroxide release when appropriately compounded to reduce pH variation and avoid excessive hydrogen peroxide levels.

Immediate oral implant placement is a widely accepted technique, known for its efficacy in reducing treatment duration, surgical visits, and overall healing time. One of the primary challenges associated with immediate implant placement is the attainment of initial stability. The inevitable loss of bone and soft tissue after extraction poses a risk to implant osseointegration in both vertical and horizontal dimensions. Guided tissue regeneration/guided bone regeneration (GTR/GBR) is a well-established method for periodontal regeneration. However, current GTR/GBR membranes lack tissue inherent regeneration properties and necessitate combination with grafts to enhance tissue recovery. In this context, biomaterials have emerged as a promising option due to their good biocompatibility, biodegradability, and bioactive properties. They present a potential alternative to standard autologous/allograft procedures. The field of biomaterials for bone regeneration has rapidly evolved, developing new guiding materials and engineering techniques. These advances have become integral in addressing tissue defects at the immediate implant site. Various materials such as bioceramics, natural polymers, and synthetic polymers have been used for tissue repair. This article undertakes an etiological examination of tissue deficiency associated with immediate implant placement. Additionally, it reviews the advantages and disadvantages of a variety of biomaterials, aiming to provide references for clinical treatment and areas for further investigation.