Unraveling the potential of M13 phages in biomedicine: Advancing drug nanodelivery and gene therapy.

M13 phages possessing filamentous phage genomes offer the benefits of selective display of molecular moieties and delivery of therapeutic agent payloads with a tolerable safety profile. M13 phage-displayed technology for resembling antigen portions led to the discovery of mimetic epitopes that applied to antibody-based therapy and could be useful in the design of anticancer vaccines. To date, the excremental experiences have engaged the M13 phage in the development of innovative biosensors for detecting biospecies, biomolecules, and human cells with an acceptable limit of detection. Addressing the emergence of antibiotic-resistant bacteria, M13 phages are potent for packaging the programmed gene editing tools, such as CRISPR/Cas, to target multiple antimicrobial genes. Moreover, their display potential in combination with nanoparticles inspires new approaches for engineering targeted theragnostic platforms targeting multiple cellular biomarkers in vivo. In this review, we present the available data on optimizing the use of bacteriophages with a focus on the to date experiences with M13 phages, either as monoagent or as part of combination regimens in the practices of biosensors, vaccines, bactericidal, modeling of specific antigen epitopes, and phage-guided nanoparticles for drug delivery systems. Despite increasing research interest, a deep understanding of the underlying biological and genetic behaviors of M13 phages is needed to enable the full potential of these bioagents in biomedicine, as discussed here. We also discuss some of the challenges that have thus far limited the development and practical marketing of M13 phages.

Targeted nanomedicines for the treatment of bone disease and regeneration.

Targeted delivery by either passive or active targeting of therapeutics to the bone is an attractive treatment for various bone related diseases such as osteoporosis, osteosarcoma, multiple myeloma, and metastatic bone tumors. Engineering novel drug delivery carriers can increase therapeutic efficacy and minimize the risk of side effects. Developmnet of nanocarrier delivery systems is an interesting field of ongoing studies with opportunities to provide more effective therapies. In addition, preclinical nanomedicine research can open new opportunities for preclinical bone-targeted drug delivery; nevertheless, further research is needed to progress these therapies towards clinical applications. In the present review, the latest advancements in targeting moieties and nanocarrier drug delivery systems for the treatment of bone diseases are summarized. We also review the regeneration capability and effective delivery of nanomedicines for orthopedic applications.

Water content for clot composition prediction in acute ischemic stroke.

BACKGROUND: Mechanical thrombectomy (MT) has become the gold standard care for treating acute ischemic stroke (AIS) due to large vessel occlusion. Emerging evidence suggests that understanding the composition of clots prior to intervention could be useful for the selection of neuroendovascular techniques, potentially improving the efficacy of treatments. However, current imaging modalities lack the ability to distinguish clot composition accurately and reliably. Since water content can influence signal intensity on CT and MRI scans, its assessment may provide indirect clues about clot composition. This study aimed to elucidate the correlation between water content and clot composition using human clots retrieved from stroke patients and experimentally generated ovine clots. MATERIALS AND METHODS: This study involved an analysis of ten clots retrieved from patients with AIS undergoing MT. Additionally, we created ten red blood cells (RBC)-rich and ten fibrin-rich ovine blood clots, which were placed in a human intracranial vascular model under realistic flow conditions. The water content and compositions of these clots were evaluated, and linear regression analyses were performed to determine the relationship between clot composition and water content. RESULTS: The regression analysis in human stroke clots revealed a significant negative association between RBC concentration and water content. We also observed a positive correlation between water content and both fibrin and platelets in ovine blood clots. Conclusion.

Devices and Techniques.

This extensive review explores the intricacies of the three principal mechanical thrombectomy techniques: the stent retriever technique, contact aspiration technique, and a combined approach, and their application in managing acute ischemic stroke. Each technique operates uniquely on the thrombus, leading to differences in their efficacy. Factors including clot size, clot stiffness, vessel tortuosity, and the angle of interaction between the aspiration catheter and the clot significantly influence these differences. Clinical trials and meta-analyses have shown the overall equivalency of these techniques for the treatments of large vessel occlusion and distal medium vessel occlusions. However, there are nuanced differences that emerge under specific clinical circumstances, highlighting the absence of a one-size-fits-all strategy in acute ischemic stroke management. We emphasize the need for future investigations to elucidate these nuances further, aiming to refine procedural strategies and individualize patient care for optimal outcomes.

Advances in 3D bioprinting for urethral tissue reconstruction.

Urethral conditions affect children and adults, increasing the risk of urinary tract infections, voiding and sexual dysfunction, and renal failure. Current tissue replacements differ from healthy urethral tissues in structural and mechanical characteristics, causing high risk of postoperative complications. 3D bioprinting can overcome these limitations through the creation of complex, layered architectures using materials with location-specific biomechanical properties. This review highlights prior research and describes the potential for these emerging technologies to address ongoing challenges in urethral tissue engineering, including biomechanical and structural mismatch, lack of individualized repair solutions, and inadequate wound healing and vascularization. In the future, the integration of 3D bioprinting technology with advanced biomaterials, computational modeling, and 3D imaging could transform personalized urethral surgical procedures.

Hemostatic patch with ultra-strengthened mechanical properties for efficient adhesion to wet surfaces.

Controlling traumatic bleeding from damaged internal organs while effectively sealing the wound is critical for saving the lives of patients. Existing bioadhesives suffer from blood incompatibility, insufficient adhesion to wet surfaces, weak mechanical properties, and complex application procedures. Here, we engineered a ready-to-use hemostatic bioadhesive with ultra-strengthened mechanical properties and fatigue resistance, robust adhesion to wet tissues within a few seconds of gentle pressing, deformability to accommodate physiological function and action, and the ability to stop bleeding efficiently. The engineered hydrogel, which demonstrated high elasticity (>900%) and toughness (>4600 kJ/m3), was formed by fine-tuning a series of molecular interactions and crosslinking mechanisms involving N-hydroxysuccinimide (NHS) conjugated alginate (Alg-NHS), poly (ethylene glycol) diacrylate (PEGDA), tannic acid (TA), and Fe3+ ions. Dual adhesive moieties including mussel-inspired pyrogallol/catechol and NHS synergistically enhanced wet tissue adhesion (>400 kPa in a wound closure test). In conjunction with physical sealing, the high affinity of TA/Fe3+ for blood could further augment hemostasis. The engineered bioadhesive demonstrated excellent in vitro and in vivo biocompatibility as well as improved hemostatic efficacy as compared to commercial Surgicel®. Overall, the hydrogel design strategy described herein holds great promise for overcoming existing obstacles impeding clinical translation of engineered hemostatic bioadhesives.

Development and optimization of an ocular hydrogel adhesive patch using definitive screening design (DSD).

Adhesive hydrogels based on chemically modified photocrosslinkable polymers with specific physicochemical properties are frequently utilized for sealing wounds or incisions. These adhesive hydrogels offer tunable characteristics such as tailorable tissue adhesion, mechanical properties, swelling ratios, and enzymatic degradability. In this study, we developed and optimized a photocrosslinkable adhesive patch, GelPatch, with high burst pressure, minimal swelling, and specific mechanical properties for application as an ocular (sclera and subconjunctival) tissue adhesive. To achieve this, we formulated a series of hydrogel patches composed of different polymers with various levels of methacrylation, molecular weights, and hydrophobic/hydrophilic properties. A computerized multifactorial definitive screening design (DSD) analysis was performed to identify the most prominent components impacting critical response parameters such as adhesion, swelling ratio, elastic modulus, and second order interactions between applied components. These parameters were mathematically processed to generate a predictive model that identifies the linear and non-linear correlations between these factors. In conclusion, an optimized formulation of GelPatch was selected based on two modified polymers: gelatin methacryloyl (GelMA) and glycidyl methacrylated hyaluronic acid (HAGM). The ex vivo results confirmed adhesion and retention of the optimized hydrogel subconjunctivally and on the sclera for up to 4 days. The developed formulation has potential to be used as an ocular sealant for quick repair of laceration type ocular injuries.

Engineering a drug eluting ocular patch for delivery and sustained release of anti-inflammatory therapeutics.

Ocular inflammation is commonly associated with eye disease or injury. Effective and sustained ocular delivery of therapeutics remains a challenge due to the eye physiology and structural barriers. Herein, we engineered a photocrosslinkable adhesive patch (GelPatch) incorporated with micelles (MCs) loaded with Loteprednol etabonate (LE) for delivery and sustained release of drug. The engineered drug loaded adhesive hydrogel, with controlled physical properties, provided a matrix with high adhesion to the ocular surfaces. The incorporation of MCs within the GelPatch enabled solubilization of LE and its sustained release within 15 days. In vitro studies showed that MC loaded GelPatch supported cell viability and growth. In addition, subcutaneous implantation of the MC loaded GelPatch in rats confirmed its in vivo biocompatibility and stability within 28 days. This non-invasive, adhesive, and biocompatible drug eluting patch can be used as a matrix for the delivery and sustained release of hydrophobic drugs.

Recent Advances in Designing Electroconductive Biomaterials for Cardiac Tissue Engineering.

Implantable cardiac patches and injectable hydrogels are among the most promising therapies for cardiac tissue regeneration following myocardial infarction. Incorporating electrical conductivity into these patches and hydrogels is found to be an efficient method to improve cardiac tissue function. Conductive nanomaterials such as carbon nanotube, graphene oxide, gold nanorod, as well as conductive polymers such as polyaniline, polypyrrole, and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate are appealing because they possess the electroconductive properties of semiconductors with ease of processing and have potential to restore electrical signaling propagation through the infarct area. Numerous studies have utilized these materials for regeneration of biological tissues that possess electrical activities, such as cardiac tissue. In this review, recent studies on the use of electroconductive materials for cardiac tissue engineering and their fabrication methods are summarized. Moreover, recent advances in developing electroconductive materials for delivering therapeutic agents as one of emerging approaches for treating heart diseases and regenerating damaged cardiac tissues are highlighted.

Designing a Nitro-Induced Sutured Biomacromolecule to Engineer Electroconductive Adhesive Hydrogels.

Nitro-functionality, with a large deficit of negative charge, embraces biological importance and has proven its therapeutic essence even in chemotherapy. Functionally, with its strong electron-withdrawing capability, nitro can manipulate the electron density of organic moieties and regulates cellular-biochemical reactions. However, the chemistry of nitro-functionality to introduce physiologically relevant macroscopic properties from the molecular skeleton is unknown. Therefore, herein, a neurotransmitter moiety, dopamine, was chemically modified with a nitro-group to explore its influence on synthesizing a multifunctional biomaterial for therapeutic applications. Chemically, while the nitro-group perturbed the aromatic electron density of nitrocatecholic domain, it facilitated the suturing of nitrocatechol moieties to regain its aromaticity through a radical transfer mechanism, forming a novel macromolecular structure. Incorporation of the sutured-nitrocatecholic strand (S-nCAT) in a gelatin-based hydrogel introduced an electroconductive microenvironment through the delocalization of π-electrons in S-nCAT, while maintaining its catechol-mediated adhesive property for tissue repairing/sealing. Meanwhile, the engineered hydrogel enriched with noncovalent interactions, demonstrated excellent mechano-physical properties to support tissue functions. Cytocompatibility of the bioadhesive was assessed with in vitro and in vivo studies, confirming its potential usage for biomedical applications. In conclusion, this novel chemical approach enabled designing a multifunctional biomaterial by manipulating the electronic properties of small bioactive molecules for various biomedical applications.

Engineering a highly elastic bioadhesive for sealing soft and dynamic tissues.

Injured tissues often require immediate closure to restore the normal functionality of the organ. In most cases, injuries are associated with trauma or various physical surgeries where different adhesive hydrogel materials are applied to close the wounds. However, these materials are typically toxic, have low elasticity, and lack strong adhesion especially to the wet tissues. In this study, a stretchable composite hydrogel consisting of gelatin methacrylol catechol (GelMAC) with ferric ions, and poly(ethylene glycol) diacrylate (PEGDA) was developed. The engineered material could adhere to the wet tissue surfaces through the chemical conjugation of catechol and methacrylate groups to the gelatin backbone. Moreover, the incorporation of PEGDA enhanced the elasticity of the bioadhesives. Our results showed that the physical properties and adhesion of the hydrogels could be tuned by changing the ratio of GelMAC/PEGDA. In addition, the in vitro toxicity tests confirmed the biocompatibility of the engineered bioadhesives. Finally, using an ex vivo lung incision model, we showed the potential application of the developed bioadhesives for sealing elastic tissues.

Engineering a naturally derived hemostatic sealant for sealing internal organs.

Controlling bleeding from a raptured tissue, especially during the surgeries, is essentially important. Particularly for soft and dynamic internal organs where use of sutures, staples, or wires is limited, treatments with hemostatic adhesives have proven to be beneficial. However, major drawbacks with clinically used hemostats include lack of adhesion to wet tissue and poor mechanics. In view of these, herein, we engineered a double-crosslinked sealant which showed excellent hemostasis (comparable to existing commercial hemostat) without compromising its wet tissue adhesion. Mechanistically, the engineered hydrogel controlled the bleeding through its wound-sealing capability and inherent chemical activity. This mussel-inspired hemostatic adhesive hydrogel, named gelatin methacryloyl-catechol (GelMAC), contained covalently functionalized catechol and methacrylate moieties and showed excellent biocompatibility both in vitro and in vivo. Hemostatic property of GelMAC hydrogel was initially demonstrated with an in vitro blood clotting assay, which showed significantly reduced clotting time compared to the clinically used hemostat, Surgicel®. This was further assessed with an in vivo liver bleeding test in rats where GelMAC hydrogel closed the incision rapidly and initiated blood coagulation even faster than Surgicel®. The engineered GelMAC hydrogel-based seaalant with excellent hemostatic property and tissue adhesion can be utilized for controlling bleeding and sealing of soft internal organs.

A new aspiration device equipped with a hydro-separator for acute ischemic stroke due to challenging soft and stiff clots.

OBJECTIVE: Fragile soft clots and stiff clots remain challenging in the treatment of acute ischemic stroke. This study aims to investigate the impact of clot stiffness on the efficacy of thrombectomy devices and a new aspiration catheter with a hydro-separator. METHODS: The Neurostar aspiration catheter has a novel hydro-separator technology that macerates clots by a stream of saline inside the catheter. The Neurostar catheter and two commercially available devices, the SOFIA aspiration catheter and Solitaire stent retriever, were tested in this study. We evaluated the efficacy of each device on clots with various stiffness in a simple in vitro model. We also assessed single-pass recanalization performance in challenging situations with large erythrocyte-rich clots and fibrin-rich clots in a realistic vascular model. RESULTS: We observed an inverse association between the clot stiffness and recanalization rates. The aspiration catheter, SOFIA ingested soft clots but not moderately stiff clots. When removing soft clots with the stent retriever, fragmentation was observed, although relatively stiff clots were well-integrated and removed. The Neurostar ingested soft clots similar to the aspiration catheter, and also aspirated stiff clots by continuous suction with hydro-separator. In the experiments with challenging clots, the Neurostar led to significantly higher recanalization rates than the stent retriever and aspiration catheter. CONCLUSIONS: The stiffness of the clots affected the efficacy of endovascular thrombectomy based on the type of device. The Neurostar catheter with hydro-separator resulted in better success rates than a commercially available aspiration catheter and stent retriever in this experimental model.

Nucleic acid-based therapeutics for dermal wound healing.

Non-healing wounds have long been the subject of scientific and clinical investigations. Despite breakthroughs in understanding the biology of delayed wound healing, only limited advances have been made in properly treating wounds. Recently, research into nucleic acids (NAs) such as small-interfering RNA (siRNA), microRNA (miRNA), plasmid DNA (pDNA), aptamers, and antisense oligonucleotides (ASOs) has resulted in the development of a latest therapeutic strategy for wound healing. In this regard, dendrimers, scaffolds, lipid nanoparticles, polymeric nanoparticles, hydrogels, and metal nanoparticles have all been explored as NA delivery techniques. However, the translational possibility of NA remains a substantial barrier. As a result, different NAs must be identified, and their distribution method must be optimized. This review explores the role of NA-based therapeutics in various stages of wound healing and provides an update on the most recent findings in the development of NA-based nanomedicine and biomaterials, which may offer the potential for the invention of novel therapies for this long-term condition. Further, the challenges and potential for miRNA-based techniques to be translated into clinical applications are also highlighted.

Magnetic nanocomposites for biomedical applications.

Tissue engineering and regenerative medicine have solved numerous problems related to the repair and regeneration of damaged organs and tissues arising from aging, illnesses, and injuries. Nanotechnology has further aided tissue regeneration science and has provided outstanding opportunities to help disease diagnosis as well as treat damaged tissues. Based on the most recent findings, magnetic nanostructures (MNSs), in particular, have emerged as promising materials for detecting, directing, and supporting tissue regeneration. There have been many reports concerning the role of these nano-building blocks in the regeneration of both soft and hard tissues, but the subject has not been extensively reviewed. Here, we review, classify, and discuss various synthesis strategies for novel MNSs used in medicine. Advanced applications of magnetic nanocomposites (MG-NCs), specifically magnetic nanostructures, are further systematically reviewed. In addition, the scientific and technical aspects of MG-NC used in medicine are discussed considering the requirements for the field. In summary, this review highlights the numerous opportunities and challenges associated with the use of MG-NCs as smart nanocomposites (NCs) in tissue engineering and regenerative medicine.

Colloidal multiscale porous adhesive (bio)inks facilitate scaffold integration.

Poor cellular spreading, proliferation, and infiltration, due to the dense biomaterial networks, have limited the success of most thick hydrogel-based scaffolds for tissue regeneration. Here, inspired by whipped cream production widely used in pastries, hydrogel-based foam bioinks are developed for bioprinting of scaffolds. Upon cross-linking, a multiscale and interconnected porous structure, with pores ranging from few to several hundreds of micrometers, is formed within the printed constructs. The effect of the process parameters on the pore size distribution and mechanical and rheological properties of the bioinks is determined. The developed foam bioinks can be easily printed using both conventional and custom-built handheld bioprinters. In addition, the foam inks are adhesive upon in situ cross-linking and are biocompatible. The subcutaneous implantation of scaffolds formed from the engineered foam bioinks showed their rapid integration and vascularization in comparison with their non-porous hydrogel counterparts. In addition, in vivo application of the foam bioink into the non-healing muscle defect of a murine model of volumetric muscle loss resulted in a significant functional recovery and higher muscle forces at 8 weeks post injury compared with non-treated controls.