Injectable Nanoengineered Adhesive Hydrogel for Treating Enterocutaneous Fistulas.

Enterocutaneous fistula (ECF) is a severe medical condition where an abnormal connection forms between the gastrointestinal tract and skin. ECFs are, in most cases, a result of surgical complications such as missed enterotomies or anastomotic leaks. The constant leakage of enteric and fecal contents from the fistula site leads to skin breakdown and increases the risk of infection. Despite advances in surgical techniques and postoperative management, ECF accounts for significant mortality rates, estimated between 15-20%, and causes debilitating morbidity. Therefore, there is a critical need for a simple and effective method to seal and heal ECF. Injectable hydrogels with combined properties of robust mechanical properties and cell infiltration/proliferation have the potential to block and heal ECF. Herein, we report the development of an injectable nanoengineered adhesive hydrogel (INAH) composed of a synthetic nanosilicate (Laponite®) and a gelatin-dopamine conjugate for treating ECF. The hydrogel undergoes fast cross-linking using a co-injection method, resulting in a matrix with improved mechanical and adhesive properties. INAH demonstrates appreciable blood clotting abilities and is cytocompatible with fibroblasts. The adhesive properties of the hydrogel are demonstrated in ex vivo adhesion models with skin and arteries, where the volume stability in the hydrated internal environment facilitates maintaining strong adhesion. In vivo assessments reveal that the INAH is biocompatible, supporting cell infiltration and extracellular matrix deposition while not forming fibrotic tissue. These findings suggest that this INAH holds promising translational potential for sealing and healing ECF.

Engineered organoids for biomedical applications.

As miniaturized and simplified stem cell-derived 3D organ-like structures, organoids are rapidly emerging as powerful tools for biomedical applications. With their potential for personalized therapeutic interventions and high-throughput drug screening, organoids have gained significant attention recently. In this review, we discuss the latest developments in engineering organoids and using materials engineering, biochemical modifications, and advanced manufacturing technologies to improve organoid culture and replicate vital anatomical structures and functions of human tissues. We then explore the diverse biomedical applications of organoids, including drug development and disease modeling, and highlight the tools and analytical techniques used to investigate organoids and their microenvironments. We also examine the latest clinical trials and patents related to organoids that show promise for future clinical translation. Finally, we discuss the challenges and future perspectives of using organoids to advance biomedical research and potentially transform personalized medicine.

Enhanced Maturation of 3D Bioprinted Skeletal Muscle Tissue Constructs Encapsulating Soluble Factor-Releasing Microparticles.

Several microfabrication technologies have been used to engineer native-like skeletal muscle tissues. However, the successful development of muscle remains a significant challenge in the tissue engineering field. Muscle tissue engineering aims to combine muscle precursor cells aligned within a highly organized 3D structure and biological factors crucial to support cell differentiation and maturation into functional myotubes and myofibers. In this study, the use of 3D bioprinting is proposed for the fabrication of muscle tissues using gelatin methacryloyl (GelMA) incorporating sustained insulin-like growth factor-1 (IGF-1)-releasing microparticles and myoblast cells. This study hypothesizes that functional and mature myotubes will be obtained more efficiently using a bioink that can release IGF-1 sustainably for in vitro muscle engineering. Synthesized microfluidic-assisted polymeric microparticles demonstrate successful adsorption of IGF-1 and sustained release of IGF-1 at physiological pH for at least 21 days. Incorporating the IGF-1-releasing microparticles in the GelMA bioink assisted in promoting the alignment of myoblasts and differentiation into myotubes. Furthermore, the myotubes show spontaneous contraction in the muscle constructs bioprinted with IGF-1-releasing bioink. The proposed bioprinting strategy aims to improve the development of new therapies applied to the regeneration and maturation of muscle tissues.

Gelatin methacryloyl and Laponite bioink for 3D bioprinted organotypic tumor modeling.

Three-dimensional (3D)in vitrotumor models that can capture the pathophysiology of human tumors are essential for cancer biology and drug development. However, simulating the tumor microenvironment is still challenging because it consists of a heterogeneous mixture of various cellular components and biological factors. In this regard, current extracellular matrix (ECM)-mimicking hydrogels used in tumor tissue engineering lack physical interactions that can keep biological factors released by encapsulated cells within the hydrogel and improve paracrine interactions. Here, we developed a nanoengineered ion-covalent cross-linkable bioink to construct 3D bioprinted organotypic tumor models. The bioink was designed to implement the tumor ECM by creating an interpenetrating network composed of gelatin methacryloyl (GelMA), a light cross-linkable polymer, and synthetic nanosilicate (Laponite) that exhibits a unique ionic charge to improve retention of biological factors released by the encapsulated cells and assist in paracrine signals. The physical properties related to printability were evaluated to analyze the effect of Laponite hydrogel on bioink. Low GelMA (5%) with high Laponite (2.5%-3.5%) composite hydrogels and high GelMA (10%) with low Laponite (1.0%-2.0%) composite hydrogels showed acceptable mechanical properties for 3D printing. However, a low GelMA composite hydrogel with a high Laponite content could not provide acceptable cell viability. Fluorescent cell labeling studies showed that as the proportion of Laponite increased, the cells became more aggregated to form larger 3D tumor structures. Reverse transcription-polymerase chain reaction (RT-qPCR) and western blot experiments showed that an increase in the Laponite ratio induces upregulation of growth factor and tissue remodeling-related genes and proteins in tumor cells. In contrast, cell cycle and proliferation-related genes were downregulated. On the other hand, concerning fibroblasts, the increase in the Laponite ratio indicated an overall upregulation of the mesenchymal phenotype-related genes and proteins. Our study may provide a rationale for using Laponite-based hydrogels in 3D cancer modeling.

Peptide Hydrogels as Immunomaterials and Their Use in Cancer Immunotherapy Delivery.

Peptide-based hydrogel biomaterials have emerged as an excellent strategy for immune system modulation. Peptide-based hydrogels are supramolecular materials that self-assemble into various nanostructures through various interactive forces (i.e., hydrogen bonding and hydrophobic interactions) and respond to microenvironmental stimuli (i.e., pH, temperature). While they have been reported in numerous biomedical applications, they have recently been deemed promising candidates to improve the efficacy of cancer immunotherapies and treatments. Immunotherapies seek to harness the body's immune system to preemptively protect against and treat various diseases, such as cancer. However, their low efficacy rates result in limited patient responses to treatment. Here, the immunomaterial's potential to improve these efficacy rates by either functioning as immune stimulators through direct immune system interactions and/or delivering a range of immune agents is highlighted. The chemical and physical properties of these peptide-based materials that lead to immuno modulation and how one may design a system to achieve desired immune responses in a controllable manner are discussed. Works in the literature that reports peptide hydrogels as adjuvant systems and for the delivery of immunotherapies are highlighted. Finally, the future trends and possible developments based on peptide hydrogels for cancer immunotherapy applications are discussed.

Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer.

The tumor microenvironment consists of diverse, complex etiological factors. The matrix component of pancreatic ductal adenocarcinoma (PDAC) plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness. Although significant efforts have been made to model desmoplastic PDAC, existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC. Here, two major components in desmoplastic pancreatic matrices, hyaluronic acid- and gelatin-based hydrogels, are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts (CAF). Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation. Higher expression levels of markers associated with proliferation, epithelial to mesenchymal transition, mechanotransduction, and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels, while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-ß1 (TGF-ß1). The proposed multicellular pancreatic tumor model, in combination with proper mechanical properties and TGF-ß1 supplement, makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors, which could be potentially applicable for realizing personalized medicine and drug testing applications.

Skin-interfaced electronics: A promising and intelligent paradigm for personalized healthcare.

Skin-interfaced electronics (skintronics) have received considerable attention due to their thinness, skin-like mechanical softness, excellent conformability, and multifunctional integration. Current advancements in skintronics have enabled health monitoring and digital medicine. Particularly, skintronics offer a personalized platform for early-stage disease diagnosis and treatment. In this comprehensive review, we discuss (1) the state-of-the-art skintronic devices, (2) material selections and platform considerations of future skintronics toward intelligent healthcare, (3) device fabrication and system integrations of skintronics, (4) an overview of the skintronic platform for personalized healthcare applications, including biosensing as well as wound healing, sleep monitoring, the assessment of SARS-CoV-2, and the augmented reality-/virtual reality-enhanced human-machine interfaces, and (5) current challenges and future opportunities of skintronics and their potentials in clinical translation and commercialization. The field of skintronics will not only minimize physical and physiological mismatches with the skin but also shift the paradigm in intelligent and personalized healthcare and offer unprecedented promise to revolutionize conventional medical practices.

Recent advances in biopolymer-based hemostatic materials.

Hemorrhage is the leading cause of trauma-related deaths, in hospital and prehospital settings. Hemostasis is a complex mechanism that involves a cascade of clotting factors and proteins that result in the formation of a strong clot. In certain surgical and emergency situations, hemostatic agents are needed to achieve faster blood coagulation to prevent the patient from experiencing a severe hemorrhagic shock. Therefore, it is critical to consider appropriate materials and designs for hemostatic agents. Many materials have been fabricated as hemostatic agents, including synthetic and naturally derived polymers. Compared to synthetic polymers, natural polymers or biopolymers, which include polysaccharides and polypeptides, have greater biocompatibility, biodegradability and processibility. Thus, in this review, we focus on biopolymer-based hemostatic agents of different forms, such as powder, particles, sponges and hydrogels. Finally, we discuss biopolymer-based hemostatic materials currently in clinical trials and offer insight into next-generation hemostats for clinical translation.

Lab-on-a-Contact Lens: Recent Advances and Future Opportunities in Diagnostics and Therapeutics.

The eye is one of the most complex organs in the human body, containing rich and critical physiological information (e.g., intraocular pressure, corneal temperature, and pH) as well as a library of metabolite biomarkers (e.g., glucose, proteins, and specific ions). Smart contact lenses (SCLs) can serve as a wearable intelligent ocular prosthetic device capable of noninvasive and continuous monitoring of various essential physical/biochemical parameters and drug loading/delivery for the treatment of ocular diseases. Advances in SCL technologies and the growing public interest in personalized health are accelerating SCL research more than ever before. Here, the current status and potential of SCL development through a comprehensive review from fabrication to applications to commercialization are discussed. First, the material, fabrication, and platform designs of the SCLs for the diagnostic and therapeutic applications are discussed. Then, the latest advances in diagnostic and therapeutic SCLs for clinical translation are reviewed. Later, the established techniques for wearable power transfer and wireless data transmission applied to current SCL devices are summarized. An outlook, future opportunities, and challenges for developing next-generation SCL devices are also provided. With the rise in interest of SCL development, this comprehensive and essential review can serve as a new paradigm for the SCL devices.

pH-Responsive doxorubicin delivery using shear-thinning biomaterials for localized melanoma treatment.

Injectable shear-thinning biomaterials (STBs) have attracted significant attention because of their efficient and localized delivery of cells as well as various molecules ranging from growth factors to drugs. Recently, electrostatic interaction-based STBs, including gelatin/LAPONITE® nanocomposites, have been developed through a simple assembly process and show outstanding shear-thinning properties and injectability. However, the ability of different compositions of gelatin and LAPONITE® to modulate doxorubicin (DOX) delivery at different pH values to enhance the effectiveness of topical skin cancer treatment is still unclear. Here, we fabricated injectable STBs using gelatin and LAPONITE® to investigate the influence of LAPONITE®/gelatin ratio on mechanical characteristics, capacity for DOX release in response to different pH values, and cytotoxicity toward malignant melanoma. The release profile analysis of various compositions of DOX-loaded STBs under different pH conditions revealed that lower amounts of LAPONITE® (6NC25) led to higher pH-responsiveness capable of achieving a localized, controlled, and sustained release of DOX in an acidic tumor microenvironment. Moreover, we showed that 6NC25 had a lower storage modulus and required lower injection forces compared to those with higher LAPONITE® ratios. Furthermore, DOX delivery analysis in vitro and in vivo demonstrated that DOX-loaded 6NC25 could efficiently target subcutaneous malignant tumors via DOX-induced cell death and growth restriction.

Recent developments in mussel-inspired materials for biomedical applications.

Over the decades, researchers have strived to synthesize and modify nature-inspired biomaterials, with the primary aim to address the challenges of designing functional biomaterials for regenerative medicine and tissue engineering. Among these challenges, biocompatibility and cellular interactions have been extensively investigated. Some of the most desirable characteristics for biomaterials in these applications are the loading of bioactive molecules, strong adhesion to moist areas, improvement of cellular adhesion, and self-healing properties. Mussel-inspired biomaterials have received growing interest mainly due to the changes in mechanical and biological functions of the scaffold due to catechol modification. Here, we summarize the chemical and biological principles and the latest advancements in production, as well as the use of mussel-inspired biomaterials. Our main focus is the polydopamine coating, the conjugation of catechol with other polymers, and the biomedical applications that polydopamine moieties are used for, such as matrices for drug delivery, tissue regeneration, and hemostatic control. We also present a critical conclusion and an inspired view on the prospects for the development and application of mussel-inspired materials.

Development of a novel label-free impedimetric electrochemical sensor based on hydrogel/chitosan for the detection of ochratoxin A.

Ochratoxin A (OTA) is one of the most abundant mycotoxins that contaminate various food products. Herein, we propose a novel label-free impedimetric electrochemical sensor consisting of chitosan/dipeptide nanofibrous hydrogel and immobilized DNA probes with OTA aptamer for the detection of OTA. The thin film of chitosan/dipeptide nanofibrous hydrogel was used as sensing interface and carrier for hybridization chain reaction (HCR) of OTA aptamer and DNA2 strand to form DNA concatemer. The concatemer was dissociated to single-stranded DNA (ssDNA) in the presence of target OTA, and the signal amplification was further implemented by introducing RecJf exonuclease, which could digest the single-stranded DNA resulting in OTA recycle. Electrochemical impedance spectroscopy (EIS) has been employed to characterize the properties of the fabricated sensor. A linear detection range of 0.1-100 ng mL-1 was obtained for OTA with a low detection limit of 0.03 ng mL-1. Furthermore, the developed sensor was demonstrated in white wine to detect OTA, indicating that the proposed impedimetric sensor has a promising potential application in the food industry.

Peptide-Polydopamine Nanocomposite Hydrogel for a Laser-Controlled Hydrophobic Drug Delivery.

Smart antibacterial systems, delivering antimicrobials in a highly controlled manner, are one strategy toward fighting the rise of antibiotic-resistant pathogens. Here, we engineer a laser-responsive antimicrobial nanocomposite hydrogel combining a peptide amphiphile and a photothermally active polydopamine nanoparticle (PDNP) to entrap the hydrophobic rifampicin within the hydrophilic hydrogel matrix. We show that the ability of the gelator to interact and retain rifampicin within the gel induced structural changes in its nanofiber network and mechanical properties. Furthermore, PDNP inclusion enabled laser-induced drug release, preventing growth of a Gram-negative E. coli. Overall, our work provides a significant advance in designing smart materials for controlled drug delivery applications.

Multi-component peptide hydrogels - a systematic study incorporating biomolecules for the exploration of diverse, tuneable biomaterials.

Peptide-based supramolecular gels can be designed to be functional "smart" materials that have applications in drug delivery, tissue engineering, and supramolecular chemistry. Although many multi-component gel systems have been designed and reported, many of these applications still rely solely on single-component gel systems which limits the functionalities of the materials. Multi-component self-assembly leads to the formation of highly ordered and complex architectures while offering the possibility to generate hydrogels with interesting properties including functional complexity and diverse morphologies. Being able to incorporate various classes of biomolecules can allow for tailoring the materials' functionalities to specific application needs. Here, a novel peptide amphiphile, myristyl-Phe-Phe (C14-FF), was synthesized and explored for hydrogel formation. The hydrogel possesses a nanofiber matrix morphology, composed of ß-sheet aggregates, a record-low gelation concentration for this class of compounds, and a unique solvent-dependent helical switch. The C14-FF hydrogel was then explored with various classes of biomolecules (carbohydrates, vitamins, proteins, building blocks of HA) to generate a multi-component library of gels that have potential to represent the complex natural extracellular matrix. Selected multi-component gels exhibit an excellent compatibility with mesenchymal stem cells showing high cell viability percentages, which holds great promise for applications in regenerative therapy.

Supramolecular Peptide Gels: Influencing Properties by Metal Ion Coordination and Their Wide-Ranging Applications.

Supramolecular gels have been an area of interest in many research fields. They provide a means to understand assembly of nanostructures, and through the use of amino acid- and peptide-based gelators they can give insights into the similar assembly pathways of their more complex structural counterparts. Bio-inspired metal coordination, such as histidine-copper coordination, in the supramolecular assembly of these gelators is one method for furthering our understanding and development of these materials. Metal-gelator coordination mimics biologically relevant metal-peptide coordination, thus influencing hydrogel self-assembly and mechanical properties, including biodegradability, biocompatibility, tunability, and recyclablity, while the metal coordination can functionalize the gels to allow for widespread applications in biomedical industries (e.g., drug delivery), waste management, and catalysis. This review aims to discuss recent insights into the supramolecular assembly of gels involving metal ions, as well as a few key areas of application using metal interactions and incorporation.

Enzyme Entrapment in Amphiphilic Myristyl-Phenylalanine Hydrogels.

Supramolecular amino acid and peptide hydrogels are functional materials with a wide range of applications, however, their ability to serve as matrices for enzyme entrapment have been rarely explored. Two amino acid conjugates were synthesized and explored for hydrogel formation. These hydrogels were characterized in terms of strength and morphology, and their ability to entrap enzymes while keeping them active and reusable was explored. It was found that the hydrogels were able to successfully entrap two common and significant enzymes-horseradish peroxidase and -amylase-thus keeping them active and stable, along with inducing recycling capabilities, which has potential to further advance the industrial biotransformation field.

Synthesis and Biochemical Evaluation of Nicotinamide Derivatives as NADH Analogue Coenzymes in Ene Reductase.

Nicotinamide and pyridine-containing conjugates have attracted a lot of attention in research as they have found use in a wide range of applications including as redox flow batteries and calcium channel blockers, in biocatalysis, and in metabolism. The interesting redox character of the compounds' pyridine/dihydropyridine system allows them to possess very similar characteristics to the natural chiral redox agents NAD+ /NADH, even mimicking their functions. There has been considerable interest in designing and synthesizing NAD+ /NADH mimetics with similar redox properties. In this research, three nicotinamide conjugates were designed, synthesized, and characterized. Molecular structures obtained through X-ray crystallography were obtained for two of the conjugates, thereby providing more detail on the bonding and structure of the compounds. The compounds were then further evaluated for biochemical properties, and it was found that one of the conjugates possessed similar functions and characteristics to the natural NADH. This compound was evaluated in the active enzyme, enoate reductase; like NADH, it was shown to help reduce the C=C double bond of three substrates and even outperformed the natural coenzyme. Kinetic data are reported.

Supramolecular Assembly of Peptide and Metallopeptide Gelators and Their Stimuli-Responsive Properties in Biomedical Applications.

Supramolecular gels are a fascinating class of soft materials that have attracted significant attention in recent years. They are composed of small molecule gelators that assemble into supramolecular network structures. The resulting space is filled with solvent. Some gel materials are able to respond to various stimuli making them attractive drug delivery vehicles and as matrices for tissue regeneration. Peptide-based gel materials are particularly attractive as they possess numerous advantages including biocompatibility and biodegradability. Stimuli-responsive peptides that alter properties as a function of pH, redox, temperature, and enzymes offer the potential to create materials with tunable characteristics. In addition, the ability of metal ions to improve the strength of gelation or act as a scaffold has become an interesting approach to develop dynamic peptide gel materials. In this review, the stimuli-responsive properties (pH, redox, temperature, and enzyme responsive properties), as well as the biocompatible/-degradable nature of the peptide gelators are highlighted. In addition, metal ions are discussed as a stimulus to enhance peptide gelation and a number of potential applications of these peptide gelators are provided with an outlook on future directions.

A Ferrocene-Tryptophan Conjugate: The Role of the Indolic Nitrogen in Supramolecular Assembly.

Bio-organometallic ferrocene-containing amino acids and peptides have been reported to form gels and are interesting to study due to their structural properties and applications for biological purposes. In this study, a ferrocene-dicarboxylic acid derivative of the dipeptide tryptophan-tryptophan was investigated. The indolic nitrogen in the amino acid tryptophan is important for biological functions due to its role in hydrogen bonding. Here, intermolecular interactions with the indolic nitrogen allow this conjugate to self-assemble into a fibrous supramolecular structure that forms a stable gel. Rheological analysis demonstrates the self-healing nature of this gel. Interestingly, X-ray analysis of this ferrocene-peptide conjugate reveals close contacts involving tryptophan, in particular the indole NH group in interactions with an adjacent neighboring molecule.