Injectable Self-Oxygenating Cardio-Protective and Tissue Adhesive Silk-Based Hydrogel for Alleviating Ischemia After Mi Injury.

Myocardial infarction (MI) is a significant cardiovascular disease that restricts blood flow, resulting in massive cell death and leading to stiff and noncontractile fibrotic scar tissue formation. Recently, sustained oxygen release in the MI area has shown regeneration ability; however, improving its therapeutic efficiency for regenerative medicine remains challenging. Here, a combinatorial strategy for cardiac repair by developing cardioprotective and oxygenating hybrid hydrogels that locally sustain the release of stromal cell-derived factor-1 alpha (SDF) and oxygen for simultaneous activation of neovascularization at the infarct area is presented. A sustained release of oxygen and SDF from injectable, mechanically robust, and tissue-adhesive silk-based hybrid hydrogels is achieved. Enhanced endothelialization under normoxia and anoxia is observed. Furthermore, there is a marked improvement in vascularization that leads to an increment in cardiomyocyte survival by ≈30% and a reduction of the fibrotic scar formation in an MI animal rodent model. Improved left ventricular systolic and diastolic functions by ≈10% and 20%, respectively, with a ≈25% higher ejection fraction on day 7 are also observed. Therefore, local delivery of therapeutic oxygenating and cardioprotective hydrogels demonstrates beneficial effects on cardiac functional recovery for reparative therapy.

Algae-Mediated Removal of Prevalent Genotoxic Antibiotics: Molecular Perspective on Algae-Bacteria Consortia and Bioreactor-Based Strategies.

Antibiotic pollution poses a potential risk of genotoxicity, as antibiotics released into the environment can induce DNA damage and mutagenesis in various organisms. This pollution, stemming from pharmaceutical manufacturing, agriculture, and improper disposal, can disrupt aquatic ecosystems and potentially impact human health through the consumption of contaminated water and food. The removal of genotoxic antibiotics using algae-mediated approaches has gained considerable attention due to its potential for mitigating the environmental and health risks associated with these compounds. The paper provides an in-depth examination of the molecular aspects concerning algae and bioreactor-driven methodologies utilized for the elimination of deleterious antibiotics. The molecular analysis encompasses diverse facets, encompassing the discernment and profiling of algae species proficient in antibiotic degradation, the explication of enzymatic degradation pathways, and the refinement of bioreactor configurations to augment removal efficacy. Emphasizing the significance of investigating algal approaches for mitigating antibiotic pollution, this paper underscores their potential as a sustainable solution, safeguarding both the environment and human health.

Self-Oxygenation of Tissues Orchestrates Full-Thickness Vascularization of Living Implants.

Bioengineering of tissues and organs has the potential to generate functional replacement organs. However, achieving the full-thickness vascularization that is required for long-term survival of living implants has remained a grand challenge, especially for clinically sized implants. During the pre-vascular phase, implanted engineered tissues are forced to metabolically rely on the diffusion of nutrients from adjacent host-tissue, which for larger living implants results in anoxia, cell death, and ultimately implant failure. Here it is reported that this challenge can be addressed by engineering self-oxygenating tissues, which is achieved via the incorporation of hydrophobic oxygen-generating micromaterials into engineered tissues. Self-oxygenation of tissues transforms anoxic stresses into hypoxic stimulation in a homogenous and tissue size-independent manner. The in situ elevation of oxygen tension enables the sustained production of high quantities of angiogenic factors by implanted cells, which are offered a metabolically protected pro-angiogenic microenvironment. Numerical simulations predict that self-oxygenation of living tissues will effectively orchestrate rapid full-thickness vascularization of implanted tissues, which is empirically confirmed via in vivo experimentation. Self-oxygenation of tissues thus represents a novel, effective, and widely applicable strategy to enable the vascularization living implants, which is expected to advance organ transplantation and regenerative medicine applications.

Modular Fabrication of Intelligent Material-Tissue Interfaces for Bioinspired and Biomimetic Devices.

One of the goals of biomaterials science is to reverse engineer aspects of human and nonhuman physiology. Similar to the body's regulatory mechanisms, such devices must transduce changes in the physiological environment or the presence of an external stimulus into a detectable or therapeutic response. This review is a comprehensive evaluation and critical analysis of the design and fabrication of environmentally responsive cell-material constructs for bioinspired machinery and biomimetic devices. In a bottom-up analysis, we begin by reviewing fundamental principles that explain materials' responses to chemical gradients, biomarkers, electromagnetic fields, light, and temperature. Strategies for fabricating highly ordered assemblies of material components at the nano to macro-scales via directed assembly, lithography, 3D printing and 4D printing are also presented. We conclude with an account of contemporary material-tissue interfaces within bioinspired and biomimetic devices for peptide delivery, cancer theranostics, biomonitoring, neuroprosthetics, soft robotics, and biological machines.

A Tumor-on-a-Chip System with Bioprinted Blood and Lymphatic Vessel Pair.

Current in vitro anti-tumor drug screening strategies are insufficiently portrayed lacking true perfusion and draining microcirculation systems, which may post significant limitation in reproducing the transport kinetics of cancer therapeutics explicitly. Herein, we report the fabrication of an improved tumor model consisting of bioprinted hollow blood vessel and lymphatic vessel pair, hosted in a three-dimensional (3D) tumor microenvironment-mimetic hydrogel matrix, termed as the tumor-on-a-chip with bioprinted blood and lymphatic vessel pair (TOC-BBL). The bioprinted blood vessel was perfusable channel with opening on both ends while the bioprinted lymphatic vessel was blinded on one end, both of which were embedded in a hydrogel tumor mass, with vessel permeability individually tunable through optimization of the composition of the bioinks. We demonstrated that systems with different combinations of these bioprinted blood/lymphatic vessels exhibited varying levels of diffusion profiles for biomolecules and anti-cancer drugs. Our TOC-BBL platform mimicking the natural pathway of drug-tumor interactions would have the drug introduced through the perfusable blood vessel, cross the vascular wall into the tumor tissue via diffusion, and eventually drained into the lymphatic vessel along with the carrier flow. Our results suggested that this unique in vitro tumor model containing the bioprinted blood/lymphatic vessel pair may have the capacity of simulating the complex transport mechanisms of certain pharmaceutical compounds inside the tumor microenvironment, potentially providing improved accuracy in future cancer drug screening.

Nanostructured Fibrous Membranes with Rose Spike-Like Architecture.

Nanoparticles have been used for engineering composite materials to improve the intrinsic properties and/or add functionalities to pristine polymers. The majority of the studies have focused on the incorporation of spherical nanoparticles within the composite fibers. Herein, we incorporate anisotropic branched-shaped zinc oxide (ZnO) nanoparticles into fibrous scaffolds fabricated by electrospinning. The addition of the branched particles resulted in their protrusion from fibers, mimicking the architecture of a rose stem. We demonstrated that the encapsulation of different-shape particles significantly influences the physicochemical and biological activities of the resultant composite scaffolds. In particular, the branched nanoparticles induced heterogeneous crystallization of the polymeric matrix and enhance the ultimate mechanical strain and strength. Moreover, the three-dimensional (3D) nature of the branched ZnO nanoparticles enhanced adhesion properties of the composite scaffolds to the tissues. In addition, the rose stem-like constructs offered excellent antibacterial activity, while supporting the growth of eukaryote cells.

Biophysicochemical perspective of nanoparticle compatibility: a critically ignored parameter in nanomedicine.

Engineered nanomaterials are increasingly used in domestic and commercial products due to the rapid growth and increasing public and industrial interests in nanotechnology. Undoubtedly there will be more exposure of living organisms and the environment to nanomaterials. Therefore, understanding the biophysicochemical interactions of nanoparticles with proteins, membranes, cells, DNA, and organelles at the nano-biointerface will help to control fundamental biological and dynamic colloidal forces to promote biocompatibility of the particles. In this article, we review how bio- and physicochemical surface characteristics at nanoscale govern particle biocompatibility for in vivo and in vitro models. We also revisit the promise and predictions gained from this understanding to design special types of nanoparticles, such as quantum dots (QDs) and superparamagnetic iron oxide nanoparticles (SPIONs), for biomedical applications. This knowledge is essential not only from the perspective of safe use of nanomaterials, but also in paving the way for nontoxic interactions with biological systems. It paves the route for safe implementation of the materials in novel biomedical diagnostics and therapeutics. We also put forward an outlook and future perspective, which are largely "ignored parameters" in nanomedicine. In conclusion, emphasis on the systematic evaluation of nanomaterial toxicity in primary cells derived from vital organs and the need to develop an international consortium for a materialomics database is encouraged.

Smart Biomaterials in Biomedical Applications: Current Advances and Possible Future Directions.

Smart biomaterials with the capacity to alter their properties in response to an outside stimulus or from within the environment around them have picked up significant attention in the biomedical community. This is primarily due to the interest in their biomedical applications that may be anticipated from them in a considerable number of dynamic structures and devices. Shape-memory materials are some of these materials that have been exclusively used for these applications. They exhibit unique structural reconfiguration features they adapt as per the provided environmental conditions and can be designed for their enhanced biocompatibility. Numerous research initiatives have focused on these smart biocompatible materials over the last few decades to enhance their biomedical applications. Shape-memory materials play a significant role in this regard to meet new surgical and medical devices' requirements for special features and utility cases. Because of the favorable design variety, different biomedical shape-memory materials can be developed by modifying their chemical and physical behaviors to accommodate the desired requirements. In this review, recent advances and characteristics of smart biomaterials for biomedical applications are described. The authors also discuss about their clinical translations in tissue engineering, drug delivery, and medical devices.

Technological Interventions Enhancing Curcumin Bioavailability in Wound-Healing Therapeutics.

Wound healing has been a challenge in the medical field. Tremendous research has been carried out to expedite wound healing by fabricating various formulations, some of which are now commercially available. However, owing to their natural source, people have been attracted to advanced formulations with herbal components. Among various herbs, curcumin has been the center of attraction from ancient times for its healing properties due to its multiple therapeutic effects, including antioxidant, antimicrobial, anti-inflammatory, anticarcinogenic, neuroprotective, and radioprotective properties. However, curcumin has a low water solubility and rapidly degrades into inactive metabolites, which limits its therapeutic efficacy. Henceforth, a carrier system is needed to carry curcumin, guard it against degradation, and keep its bioavailability and effectiveness. Different formulations with curcumin have been synthesized, and exist in the form of various synthetic and natural materials, including nanoparticles, hydrogels, scaffolds, films, fibers, and nanoemulgels, improving its bioavailability dramatically. This review discusses the advances in different types of curcumin-based formulations used in wound healing in recent times, concentrating on its mechanisms of action and discussing the updates on its application at several stages of the wound healing process. Impact statement Curcumin is a herbal compound extracted from turmeric root and has been used since time immemorial for its health benefits including wound healing. In clinical formulations, curcumin shows low bioavailability, which mainly stems from the way it is delivered in the body. Henceforth, a carrier system is needed to carry curcumin, guard it against degradation, while maintaining its bioavailability and therapeutic efficacy. This review offers an overview of the advanced technological interventions through tissue engineering approaches to efficiently utilize curcumin in different types of wound healing applications.

Multicomponent decellularized extracellular matrix of caprine small intestine submucosa based bioactive hydrogel promoting full-thickness burn wound healing in rabbits.

Effective treatment for full-thickness burn wounds has remained challenging for clinicians. Among various strategies, extracellular gel-based dressing materials have gained attention to promote effective and rapid wound healing. These gel-based materials are porous and have antioxidant, antibacterial, hydrophilic, biodegradation, and biocompatible properties and hence can be used to alleviate burn wound healing. In concurrence with these findings, the present study evaluates thermo-responsive and self-assembled decellularized extracellular matrix (ECM) of caprine small intestine submucosa (DG-SIS) gel-based dressing material for burn wound healing. To expedite healing and efficiently tackle excessive free radicals and bioburden at the burn wound site, DG-SIS gel is fortified with antibacterial components (zinc oxide nanoparticles; ZnO) and a potent antioxidant agent (Vitamin-C;Vt-C). ZnO- and Vt-C-enriched DG-SIS (DG-SIS/ZnO/Vt-C) gels significantly increased the antioxidant and antibacterial activity of the therapeutic hydrogel. Additionally, the fabricated DG-SIS/ZnO/Vt-C bioactive gel resulted in significant full-thickness burn wound contraction (97.75 % in 14 days), a lower inflammatory effect, and enhanced angiogenesis with the highest collagen synthesis (1.22 µg/mg in 14 days) at the wound site. The outcomes from this study demonstrate a synergistic effect of ZnO/Vt-C in the bioactive gel as an effective and inexpensive therapeutic approach for full-thickness burn wound treatment.

Noninvasive and Continuous Monitoring of On-Chip Stem Cell Osteogenesis Using a Reusable Electrochemical Immunobiosensor.

Noninvasive monitoring of biofabricated tissues during the biomanufacturing process is needed to obtain reproducible, healthy, and functional tissues. Measuring the levels of biomarkers secreted from tissues is a promising strategy to understand the status of tissues during biofabrication. Continuous and real-time information from cultivated tissues enables users to achieve scalable manufacturing. Label-free biosensors are promising candidates for detecting cell secretomes since they can be noninvasive and do not require labor-intensive processes such as cell lysing. Moreover, most conventional monitoring techniques are single-use, conducted at the end of the fabrication process, and, challengingly, are not permissive to in-line and continual detection. To address these challenges, we developed a noninvasive and continual monitoring platform to evaluate the status of cells during the biofabrication process, with a particular focus on monitoring the transient processes that stem cells go through during in vitro differentiation over extended periods. We designed and evaluated a reusable electrochemical immunosensor with the capacity for detecting trace amounts of secreted osteogenic markers, such as osteopontin (OPN). The sensor has a low limit of detection (LOD), high sensitivity, and outstanding selectivity in complex biological media. We used this OPN immunosensor to continuously monitor on-chip osteogenesis of human mesenchymal stem cells (hMSCs) cultured 2D and 3D hydrogel constructs inside a microfluidic bioreactor for more than a month and were able to observe changing levels of OPN secretion during culture. The proposed platform can potentially be adopted for monitoring a variety of biological applications and further developed into a fully automated system for applications in advanced cellular biomanufacturing.

Dual cross-linked gellan gum/gelatin-based multifunctional nanocomposite hydrogel scaffold for full-thickness wound healing.

Biological macromolecules are excellent materials for wound dressing owing to their similar structure to the extracellular matrix and adjustable physicochemical properties. This research focuses on fabricating biological macromolecule-based hydrogel with desirable antibacterial, antioxidant, controlled drug release, cytocompatibility, and wound healing properties. Herein, different concentrations of nanoceria (NC) and flurbiprofen (FLU) drug-loaded gellan gum/gelatin (GG/Ge) based dual crosslinked (Ionic and EDC/NHS coupling) hydrogels were engineered. All fabricated hydrogels were hydrophilic, biodegradable, good strength, porous, antioxidant, hemocompatible and cytocompatible. Among all, hydrogel loaded with 500 µg/ml NC (GG/Ge/NC@FLU) exhibited desirable antioxidant, antibacterial (killed Staphylococcus aureus and Escherichia coli within 12 h), hemocompatible, cytocompatible, supports oxidative-stressed L929 cell growth and acted as a controlled release matrix for FLU, following Fickian diffusion, Peppas Sahlin and Korsmeyer-Peppas drug release models. Furthermore, nanocomposite hydrogel (GG/Ge/NC@FLU)-treated wounds of rats on day 14 demonstrated significantly higher collagen synthesis, nearly 100 % wound contractions, and efficiently decreased the expression of TNF-α and IL-1 while increasing the production of IL-10 and TNF-ß3, indicating antiinflammatory activity, and effectively reduced the expression of VEGF gene indicating effective angiogenesis than all other controls. In conclusion, the fabricated multifunctional GG/Ge/NC@FLU nanocomposite hydrogel shows promising potential for effectively treating full-thickness wound healing in a rat model.

Self-oxygenation of engineered living tissues orchestrates osteogenic commitment of mesenchymal stem cells.

Oxygenating biomaterials can alleviate anoxic stress, stimulate vascularization, and improve engraftment of cellularized implants. However, the effects of oxygen-generating materials on tissue formation have remained largely unknown. Here, we investigate the impact of calcium peroxide (CPO)-based oxygen-generating microparticles (OMPs) on the osteogenic fate of human mesenchymal stem cells (hMSCs) under a severely oxygen deficient microenvironment. To this end, CPO is microencapsulated in polycaprolactone to generate OMPs with prolonged oxygen release. Gelatin methacryloyl (GelMA) hydrogels containing osteogenesis-inducing silicate nanoparticles (SNP hydrogels), OMPs (OMP hydrogels), or both SNP and OMP (SNP/OMP hydrogels) are engineered to comparatively study their effect on the osteogenic fate of hMSCs. OMP hydrogels associate with improved osteogenic differentiation under both normoxic and anoxic conditions. Bulk mRNAseq analyses suggest that OMP hydrogels under anoxia regulate osteogenic differentiation pathways more strongly than SNP/OMP or SNP hydrogels under either anoxia or normoxia. Subcutaneous implantations reveal a stronger host cell invasion in SNP hydrogels, resulting in increased vasculogenesis. Furthermore, time-dependent expression of different osteogenic factors reveals progressive differentiation of hMSCs in OMP, SNP, and SNP/OMP hydrogels. Our work demonstrates that endowing hydrogels with OMPs can induce, improve, and steer the formation of functional engineered living tissues, which holds potential for numerous biomedical applications, including tissue regeneration and organ replacement therapy.

Microfluidic fabrication of lipid nanoparticles for the delivery of nucleic acids.

Gene therapy has emerged as a potential platform for treating several dreaded and rare diseases that would not have been possible with traditional therapies. Viral vectors have been widely explored as a key platform for gene therapy due to their ability to efficiently transport nucleic acid-based therapeutics into the cells. However, the lack of precision in their delivery has led to several off-target toxicities. As such, various strategies in the form of non-viral gene delivery vehicles have been explored and are currenlty employed in several therapies including the SARS-CoV-2 vaccine. In this review, we discuss the opportunities lipid nanoparticles (LNPs) present for efficient gene delivery. We also discuss various synthesis strategies via microfluidics for high throughput fabrication of non-viral gene delivery vehicles. We conclude with the recent applications and clinical trials of these vehicles for the delivery of different genetic materials such as CRISPR editors and RNA for different medical conditions ranging from cancer to rare diseases.

Emerging Biopolymer-Based Bioadhesives.

Bioadhesives have been widely used in healthcare and biomedical applications due to their ease-of-operation for wound closure and repair compared to conventional suturing and stapling. However, several challenges remain for developing ideal bioadhesives, such as unsatisfied mechanical properties, non-tunable biodegradability, and limited biological functions. Considering these concerns, naturally derived biopolymers have been considered good candidates for making bioadhesives owing to their ready availability, facile modification, tunable mechanical properties, and desired biocompatibility and biodegradability. Over the past several years, remarkable progress has been made on biopolymer-based adhesives, covering topics from novel materials designs and advanced processing to clinical translation. The developed bioadhesives have been applied for diverse applications, including tissue adhesion, hemostasis, antimicrobial, wound repair/tissue regeneration, and skin-interfaced bioelectronics. Here in this comprehensive review, recent progress on biopolymer-based bioadhesives is summarized with focuses on clinical translations and multifunctional bioadhesives. Furthermore, challenges and opportunities such as weak adhesion strength at the hydrated state, mechanical mismatch with tissues, and unfavorable immune responses are discussed with an aim to facilitate the future development of high-performance biopolymer-based bioadhesives.

Immunomodulating Hydrogels as Stealth Platform for Drug Delivery Applications.

Non-targeted persistent immune activation or suppression by different drug delivery platforms can cause adverse and chronic physiological effects including cancer and arthritis. Therefore, non-toxic materials that do not trigger an immunogenic response during delivery are crucial for safe and effective in vivo treatment. Hydrogels are excellent candidates that can be engineered to control immune responses by modulating biomolecule release/adsorption, improving regeneration of lymphoid tissues, and enhancing function during antigen presentation. This review discusses the aspects of hydrogel-based systems used as drug delivery platforms for various diseases. A detailed investigation on different immunomodulation strategies for various delivery options and deliberate upon the outlook of such drug delivery platforms are conducted.

Enzyme-Mediated Alleviation of Peroxide Toxicity in Self-Oxygenating Biomaterials.

Oxygen releasing biomaterials can facilitate the survival of living implants by creating environments with a viable oxygen level. Hydrophobic oxygen generating microparticles (HOGMPs) encapsulated calcium peroxide (CPO) have recently been used in tissue engineering to release physiologically relevant amounts of oxygen for several weeks. However, generating oxygen using CPO is mediated via the generation of toxic levels of hydrogen peroxide (H2 O2 ). The incorporation of antioxidants, such as catalases, can potentially reduce H2 O2 levels. However, the formulation in which catalases can most effectively scavenge H2 O2 within oxygen generating biomaterials has remained unexplored. In this study, three distinct catalase incorporation methods are compared based on their ability to decrease H2 O2 levels. Specifically, catalase is incorporated within HOGMPs, or absorbed onto HOGMPs, or freely laden into the hydrogel entrapping HOGMPs and compared with control without catalase. Supplementation of free catalase in an HOGMP-laden hydrogel significantly decreases H2 O2 levels reflecting a higher cellular viability and metabolic activity of all the groups. An HOGMP/catalase-laden hydrogel precursor solution containing cells is used as an oxygenating bioink allowing improved viability of printed constructs under severe hypoxic conditions. The combination of HOGMPs with a catalase-laden hydrogel has the potential to decrease peroxide toxicity of oxygen generating tissues.

Tunable and Compartmentalized Multimaterial Bioprinting for Complex Living Tissue Constructs.

Recapitulating inherent heterogeneity and complex microarchitectures within confined print volumes for developing implantable constructs that could maintain their structure in vivo has remained challenging. Here, we present a combinational multimaterial and embedded bioprinting approach to fabricate complex tissue constructs that can be implanted postprinting and retain their three-dimensional (3D) shape in vivo. The microfluidics-based single nozzle printhead with computer-controlled pneumatic pressure valves enables laminar flow-based voxelation of up to seven individual bioinks with rapid switching between various bioinks that can solve alignment issues generated during switching multiple nozzles. To improve the spatial organization of various bioinks, printing fidelity with the z-direction, and printing speed, self-healing and biodegradable colloidal gels as support baths are introduced to build complex geometries. Furthermore, the colloidal gels provide suitable microenvironments like native extracellular matrices (ECMs) for achieving cell growths and fast host cell invasion via interconnected microporous networks in vitro and in vivo. Multicompartment microfibers (i.e., solid, core-shell, or donut shape), composed of two different bioink fractions with various lengths or their intravolume space filled by two, four, and six bioink fractions, are successfully printed in the ECM-like support bath. We also print various acellular complex geometries such as pyramids, spirals, and perfusable branched/linear vessels. Successful fabrication of vascularized liver and skeletal muscle tissue constructs show albumin secretion and bundled muscle mimic fibers, respectively. The interconnected microporous networks of colloidal gels result in maintaining printed complex geometries while enabling rapid cell infiltration, in vivo.

Correction: Diniz et al. Silver Nanoparticles-Composing Alginate/Gelatine Hydrogel Improves Wound Healing In Vivo. Nanomaterials 2020, 10, 390.

In the original publication, there was a mistake in Figure 6 as published [...].