Search

Bacterial nanocellulose (BNC) is a durable, flexible, and dynamic biomaterial capable of serving a wide variety of fields, sectors, and applications within biotechnology, healthcare, electronics, agriculture, fashion, and others. BNC is produced spontaneously in carbohydrate-rich bacterial culture media, forming a cellulosic pellicle via a nanonetwork of fibrils extruded from certain genera. Herein, we demonstrate engineering BNC-based scaffolds with tunable physical and mechanical properties through postprocessing. Human skeletal muscle myoblasts (HSMMs) were cultured on these scaffolds, and in vitro electrical stimulation was applied to promote cellular function for tissue engineering applications. We compared physiologic maturation markers of human skeletal muscle myoblast development using a 2.5-dimensional culture paradigm in fabricated BNC scaffolds, compared to two-dimensional (2D) controls. We demonstrate that the culture of human skeletal muscle myoblasts on BNC scaffolds developed under electrical stimulation produced highly aligned, physiologic morphology of human skeletal muscle myofibers compared to unstimulated BNC and standard 2D culture. Furthermore, we compared an array of metrics to assess the BNC scaffold in a rigorous head-to-head study with commercially available, clinically approved matrices, Kerecis Omega3 Wound Matrix (Marigen) and Phoenix as well as a gelatin methacryloyl (GelMA) hydrogel. The BNC scaffold outcompeted industry standard matrices as well as a 20% GelMA hydrogel in durability and sustained the support of human skeletal muscle myoblasts in vitro. This work offers a robust demonstration of BNC scaffold cytocompatibility with human skeletal muscle cells and sets the basis for future work in healthcare, bioengineering, and medical implant technological development.

Blood loss by hemorrhaging wounds accounts for over one-third of ∼5 million trauma fatalities worldwide every year. If not controlled in a timely manner, exsanguination can take lives within a few minutes. Developing new biomaterials that are easy to use by non-expert patients and promote rapid blood coagulation is an unmet medical need. Here, biocompatible, and biodegradable microneedle arrays (MNAs) based on gelatin methacryloyl (GelMA) biomaterial hybridized with silicate nanoplatelets (SNs) are developed for hemorrhage control. The SNs render the MNAs hemostatic, while the needle-shaped structure increases the contact area with blood, synergistically accelerating the clotting time from 11.5 min to 1.3 min in vitro. The engineered MNAs reduce bleeding by ∼92% compared with the untreated injury group in a rat liver bleeding model. SN-containing MNAs outperform the hemostatic effect of needle-free patches and a commercial hemostat in vivo viacombining micro- and nanoengineered features. Furthermore, the tissue adhesive properties and mechanical interlocking support the suitability of MNAs for wound closure applications. These hemostatic MNAs may enable rapid hemorrhage control, particularly for patients in developing countries or remote areas with limited or no immediate access to hospitals.

Metal additive manufacturing (AM) has led to an evolution in the design and fabrication of hard tissue substitutes, enabling personalized implants to address each patient's specific needs. In addition, internal pore architectures integrated within additively manufactured scaffolds, have provided an opportunity to further develop and engineer functional implants for better tissue integration, and long-term durability. In this review, the latest advances in different aspects of the design and manufacturing of additively manufactured metallic biomaterials are highlighted. After introducing metal AM processes, biocompatible metals adapted for integration with AM machines are presented. Then, we elaborate on the tools and approaches undertaken for the design of porous scaffold with engineered internal architecture including, topology optimization techniques, as well as unit cell patterns based on lattice networks, and triply periodic minimal surface. Here, the new possibilities brought by the functionally gradient porous structures to meet the conflicting scaffold design requirements are thoroughly discussed. Subsequently, the design constraints and physical characteristics of the additively manufactured constructs are reviewed in terms of input parameters such as design features and AM processing parameters. We assess the proposed applications of additively manufactured implants for regeneration of different tissue types and the efforts made towards their clinical translation. Finally, we conclude the review with the emerging directions and perspectives for further development of AM in the medical industry.

Laser additive manufacturing has led to a paradigm shift in the design of next-generation customized porous implants aiming to integrate better with the surrounding bone. However, conflicting design criteria have limited the development of fully functional porous implants; increasing porosity improves body fluid/cell-laden prepolymer permeability at the expense of compromising mechanical stability. Here, functionally gradient porosity implants and scaffolds designed based on interconnected triply periodic minimal surfaces (TPMS) are demonstrated. High local porosity is defined at the implant/tissue interface aiming to improve the biological response. Gradually decreasing porosity from the surface to the center of the porous constructs provides mechanical strength in selective laser melted Ti–6Al–4V implants. The effect of unit cell size is studied to discover the printability limit where the specific surface area is maximized. Furthermore, mechanical studies on the unit cell topology effects suggest that the bending-dominated architectures can provide significantly enhanced strength and deformability, compared to stretching-dominated architectures. A finite element (FE) model developed also showed great predictability (within ∼13%) of the mechanical responses of implants to physical activities. Finally, in vitrobiocompatibility studies were conducted for two-dimensional (2D) and three-dimensional (3D) cases. The results of the 2D in conjunction with surface roughness show favored physical cell attachment on the implant surface. Also, the results of the 3D biocompatibility study for the scaffolds incorporated with a cell-laden gelatin methacryloyl (GelMA) hydrogel show excellent viability. The design procedure proposed here provides new insights into the development of porous hip implants with simultaneous high mechanical and biological responses.

Inorganic/organic hybrid nanosystems have been increasingly developed for their versatility and efficacy at overcoming obstacles not readily surmounted by nonhybridized counterparts. Currently, hybrid nanosystems are implemented for gene therapy, drug delivery, and phototherapy in addition to tissue regeneration, vaccines, antibacterials, biomolecule detection, imaging probes, and theranostics. Though diverse, these nanosystems can be classified according to foundational inorganic/organic components, accessory moieties, and architecture of hybridization. Within this Review, we begin by providing a historical context for the development of biomedical hybrid nanosystems before describing the properties, synthesis, and characterization of their component building blocks. Afterward, we introduce the architectures of hybridization and highlight recent biomedical nanosystem developments by area of application, emphasizing hybrids of distinctive utility and innovation. Finally, we draw attention to ongoing clinical trials before recapping our discussion of hybrid nanosystems and providing a perspective on the future of the field.

Three-dimensional flexible porous conductors have significantly advanced wearable sensors and stretchable devices because of their specific high surface area. Dip coating of porous polymers with graphene is a facile, low cost, and scalable approach to integrate conductive layers with the flexible polymer substrate platforms; however, the products often suffer from nanoparticle delamination and overtime decay. Here, a fabrication scheme based on accessible methods and safe materials is introduced to surface-dope porous silicone sensors with graphene nanoplatelets. The sensors are internally shaped with ordered, interconnected, and tortuous internal geometries (i.e., triply periodic minimal surfaces) using fused deposition modeling (FDM) 3D-printed sacrificial molds. The molds were dip coated to transfer-embed graphene onto the silicone rubber (SR) surface. The presented procedure exhibited a stable coating on the porous silicone samples with long-term electrical resistance durability over ∼12 months period and high resistance against harsh conditions (exposure to organic solvents). Besides, the sensors retained conductivity upon severe compressive deformations (over 75% compressive strain) with high strain-recoverability and behaved robustly in response to cyclic deformations (over 400 cycles), temperature, and humidity. The sensors exhibited a gauge factor as high as 10 within the compressive strain range of 2–10%. Given the tunable sensitivity, the engineered biocompatible and flexible devices captured movements as rigorous as walking and running to the small deformations resulted by human pulse.

Hemorrhage and bacterial infections are major hurdles in the management of life‐threatening surgical wounds. Most bioadhesives for wound closure lack sufficient hemostatic and antibacterial properties. Furthermore, they suffer from weak sealing efficacy, particularly for stretchable organs, such as the lung and bladder. Accordingly, there is an unmet need for mechanically robust hemostatic sealants with simultaneous antibacterial effects. Here, an injectable, photocrosslinkable, and stretchable hydrogel sealant based on gelatin methacryloyl (GelMA), supplemented with antibacterial zinc ferrite (ZF) nanoparticles and hemostatic silicate nanoplatelets (SNs) for rapid blood coagulation is nanoengineered. The hydrogel reduces the in vitro viability of Staphylococcus aureusby more than 90%. The addition of SNs (2% w/v) and ZF nanoparticles (1.5 mg mL−1) to GelMA (20% w/v) improves the burst pressure of perforated ex vivo porcine lungs by more than 40%. Such enhancement translated to ≈250% improvement in the tissue sealing capability compared with a commercial hemostatic sealant, Evicel. Furthermore, the hydrogels reduce bleeding by ≈50% in rat bleeding models. The nanoengineered hydrogel may open new translational opportunities for the effective sealing of complex wounds that require mechanical flexibility, infection management, and hemostasis. An injectable, photocrosslinkable, and stretchable tissue sealant is developed using a gelatin methacryloyl hydrogel, supplemented with zinc ferrite nanoparticles and silicate nanoplatelets. It improves tissue adhesion by ≈250% compared with a commercial sealant and reduces bleeding by ≈50% in rat models. This engineered hydrogel platform may open new translational opportunities for the effective sealing of complex wounds that require mechanical flexibility, infection management, and hemostasis.

Bioadhesives In article 2301551, by Han‐Jun Kim, Amir Sheikhi, Ali Khademhosseini, and co‐workers, an injectable, photocrosslinkable, and stretchable tissue sealant is developed using a gelatin methacryloyl hydrogel, supplemented with zinc ferrite nanoparticles and silicate nanoplatelets. It improves tissue adhesion by ≈250% compared with a commercial sealant and reduces bleeding by ≈50% in rat models. This engineered hydrogel platform may open new translational opportunities for the effective sealing of complex wounds that require mechanical flexibility, infection management, and hemostasis.

The natural local porosity variation in the native tissue can be replicated by graded porosity scaffolds. Scaffolds with radial porosity distribution can be a solution to improve both mechanical and biological functions of the biomimetic scaffolds. In the present study, fluid permeability as a quantitative indicator of biological performance is studied numerically and experimentally for different pore shapes and porosity distribution patterns in the scaffolds designed on the basis of triply periodic minimal surfaces (TPMSs). Among the uniform porosity scaffolds, those designed on the basis of P* (P surface) and Y** (G surface) showed the highest permeability. In the radially graded porosity scaffolds with linear porosity distribution, permeability was found to be about twice more sensitive to the peripheral porosity than the porosity at the center. The results suggest that the permeability-gradient parameter relationships can follow different trends depending on the pore shape as opposed to the conventional uniform porosity scaffolds. This implies the need for the design maps that were developed to choose appropriate scaffold pore design parameters. Finally, experimental permeability measurement was performed via a constant head permeability test, and the effect of test parameters (i.e., fluid height) was discussed.

Mussel‐inspired catechol‐functionalization of degradable natural biomaterials has garnered significant interest as an approach to achieve bioadhesion for sutureless wound closure. However, conjugation capacity in standard coupling reactions, such as carbodiimide chemistry, is limited by low yield and lack of abundant conjugation sites. Here, a simple oxidative polymerization step before conjugation of catechol‐carrying molecules (i.e., 3,4‐dihydroxy‐l‐phenylalanine, l‐DOPA) as a potential approach to amplify catechol function in bioadhesion of natural gelatin biomaterials is proposed. Solutions of gelatin modified with poly(l‐DOPA) moieties (GelDOPA) are characterized by faster physical gelation and increased viscosity, providing better wound control on double‐curved tissue surfaces compared to those of l‐DOPA‐conjugated gelatin. Physical hydrogels treated topically with low concentrations of NaIO4solutions are crosslinked on‐demand via through‐thickness diffusion. Poly(l‐DOPA) conjugates enhance crosslinking density compared to l‐DOPA conjugated gelatin, resulting in lower swelling and enhanced cohesion in physiological conditions. Together with cohesion, more robust bioadhesion at body temperature is achieved by poly(l‐DOPA) conjugates, exceeding those of commercial sealants. Further, poly(l‐DOPA) motifs introduced photothermal responsiveness via near‐infrared (NIR) irradiation for controlled drug release and potential applications in photothermal therapy. The above functionalities, along with antibacterial activity, render the proposed approach an effective biomaterial design strategy for wound closure applications. Bioadhesives are leveraged by catecholic modification of natural biomacromolecules such as gelatin. Currently, available chemistries for catechol functionalization are limited by low yields. This study proposes the chemical conjugation of polycatecholic compounds derived from 3,4‐dihydroxy‐l‐phenylalanine (l‐DOPA) to boost their function for accelerated thermal gelation (better controllability), tough bioadhesion, and near‐infrared (NIR) responsiveness for photothermal therapy applications.

Bioadhesives In article 2203404by Nasim Annabi, Ali Khademhosseini, and Paul S. Weiss and co‐workers, an efficient chemical route for mussel‐inspired functionalization of natural biomacromolecules is developed to enhance sutureless sealing of surgical wounds. Compared to standard catechol functionalization, poly(catechol) modification of gelatin biomacromolecules leads to injectable bioglues with rapid gelation for hemorrhage control, tough bioadhesion, and rapid infrared responsiveness.

Injectable Hydrogels The coil structure represents the synthetic chemical composition of the featured biomaterial. The fluid network is temperature responsive and transitions into an adhesive hydrogel matrix upon administration. The resulting scaffold moulds within any defect and provides a regenerative network for cell in growth and subsequent tissue regeneration. The work represented here can be found in article 2201714by Ali Fathi, Fariba Dehghani, and co‐workers.

Injectable hydrogels can support the body's innate healing capability by providing a temporary matrix for host cell ingrowth and neovascularization. The clinical adoption of current injectable systems remains low due to their cumbersome preparation requirements, device malfunction, product dislodgment during administration, and uncontrolled biological responses at the treatment site. To address these challenges, a fully synthetic and ready‐to‐use injectable biomaterial is engineered that forms an adhesive hydrogel that remains at the administration site regardless of defect anatomy. The product elicits a negligible local inflammatory response and fully resorbs into nontoxic components with minimal impact on internal organs. Preclinical animal studies confirm that the engineered hydrogel upregulates the regeneration of both soft and hard tissues by providing a temporary matrix to support host cell ingrowth and neovascularization. In a pilot clinical trial, the engineered hydrogel is successfully administered to a socket site post tooth extraction and forms adhesive hydrogel that stabilizes blood clot and supports soft and hard tissue regeneration. Accordingly, this injectable hydrogel exhibits high therapeutic potential and can be adopted to address multiple unmet needs in different clinical settings. A fully synthetic and ready‐to‐use injectable solution is engineered that forms an adhesive hydrogel in contact with body temperature. The hydrogel provides a temporary matrix for host cell ingrowth and tissue regeneration. Preclinical and clinical results show the potential of the technology to address multiple unmet needs in different clinical settings.

Interconnected pathways in 3D bioartificial organs are essential to retaining cell activity in thick functional 3D tissues. 3D bioprinting methods have been widely explored in biofabrication of functionally patterned tissues; however, these methods are costly and confined to thin tissue layers due to poor control of low‐viscosity bioinks. Here, cell‐laden hydrogels that could be precisely patterned via water‐soluble gelatin templates are constructed by economical extrusion 3D printed plastic templates. Tortuous co‐continuous plastic networks, designed based on triply periodic minimal surfaces (TPMS), serve as a sacrificial pattern to shape the secondary sacrificial gelatin templates. These templates are eventually used to form cell‐encapsulated gelatin methacryloyl (GelMA) hydrogel scaffolds patterned with the complex interconnected pathways. The proposed fabrication process is compatible with photo‐crosslinkable hydrogels wherein prepolymer casting enables incorporation of high cell populations with high viability. The cell‐laden hydrogel constructs are characterized by robust mechanical behavior. In vivo studies demonstrate a superior cell ingrowth into the highly permeable constructs compared to the bulk hydrogels. Perfusable complex interconnected networks within cell‐encapsulated hydrogels may assist in engineering thick and functional tissue constructs through the permeable internal channels for efficient cellular activities in vivo. A biocompatible, economic, and robust biofabrication process is developed to form complex shapes and internal perfusable channels in multilayered thick tissue constructs made from extracellular matrix mimicking soft hydrogels (i.e., gelatin methacryloyl, GelMA). Cell‐laden GelMA hydrogels with interconnected pores demonstrate excellent mechanical tunability and support cell function in vitro and in vivo.

3D Bioprinting Vascularization is key to the prolonged functionality of the organs. Template‐assisted bioprinting enables biofabrication of stand‐alone thick tissues with complex vascularized networks. In article number 2102123by Ehsan Toyserkani, Ali Khademhosseini, and co‐workers, an indirect printing strategy not only eliminates the need for costly 3D bioprinters, but also allows integration of living cells within the extracellular matrix‐mimicking hydrogel matrices.

Hydrogel patches with high toughness, stretchability, and adhesive properties are critical to healthcare applications including wound dressings and wearable devices. Gelatin methacryloyl (GelMA) provides a highly biocompatible and accessible hydrogel platform. However, low tissue adhesion and poor mechanical properties of cross-linked GelMA patches (i.e., brittleness and low stretchability) have been major obstacles to their application for sealing and repair of wounds. Here, we show that adding dopamine (DA) moieties in larger quantities than those of conjugated counterparts to the GelMA prepolymer solution followed by alkaline DA oxidation could result in robust mechanical and adhesive properties in GelMA-based hydrogels. In this way, cross-linked patches with ∼140% stretchability and ∼19 000 J/m3toughness, which correspond to ∼5.7 and ∼3.3× improvement, respectively, compared to that of GelMA controls, were obtained. The DA oxidization in the prepolymer solution was found to play an important role in activating adhesive properties of cross-linked GelMA patches (∼4.0 and ∼6.9× increase in adhesion force under tensile and shear modes, respectively) due to the presence of reactive oxidized quinone species. We further conducted a parametric study on the factors such as UV light parameters, the photoinitiator type (i.e., lithium phenyl-2,4,6-trimethylbenzoylphosphinate, LAP, versus2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone, Irgacure 2959), and alkaline DA oxidation to tune the cross-linking density and thereby hydrogel compliance for better adhesive properties. The superior adhesion performance of the resulting hydrogel along with in vitrocytocompatibility demonstrated its potential for use in skin-attachable substrates.