Engineered Hemostatic Biomaterials for Sealing Wounds.

Hemostatic biomaterials show great promise in wound control for the treatment of uncontrolled bleeding associated with damaged tissues, traumatic wounds, and surgical incisions. A surge of interest has been directed at boosting hemostatic properties of bioactive materials via mechanisms triggering the coagulation cascade. A wide variety of biocompatible and biodegradable materials has been applied to the design of hemostatic platforms for rapid blood coagulation. Recent trends in the design of hemostatic agents emphasize chemical conjugation of charged moieties to biomacromolecules, physical incorporation of blood-coagulating agents in biomaterials systems, and superabsorbing materials in either dry (foams) or wet (hydrogel) states. In addition, tough bioadhesives are emerging for efficient and physical sealing of incisions. In this Review, we highlight the biomacromolecular design approaches adopted to develop hemostatic bioactive materials. We discuss the mechanistic pathways of hemostasis along with the current standard experimental procedures for characterization of the hemostasis efficacy. Finally, we discuss the potential for clinical translation of hemostatic technologies, future trends, and research opportunities for the development of next-generation surgical materials with hemostatic properties for wound management.

Bio-macromolecular design roadmap towards tough bioadhesives.

Emerging sutureless wound-closure techniques have led to paradigm shifts in wound management. State-of-the-art biomaterials offer biocompatible and biodegradable platforms enabling high cohesion (toughness) and adhesion for rapid bleeding control as well as robust attachment of implantable devices. Tough bioadhesion stems from the synergistic contributions of cohesive and adhesive interactions. This Review provides a biomacromolecular design roadmap for the development of tough adhesive surgical sealants. We discuss a library of materials and methods to introduce toughness and adhesion to biomaterials. Intrinsically tough and elastic polymers are leveraged primarily by introducing strong but dynamic inter- and intramolecular interactions either through polymer chain design or using crosslink regulating additives. In addition, many efforts have been made to promote underwater adhesion via covalent/noncovalent bonds, or through micro/macro-interlock mechanisms at the tissue interfaces. The materials settings and functional additives for this purpose and the related characterization methods are reviewed. Measurements and reporting needs for fair comparisons of different materials and their properties are discussed. Finally, future directions and further research opportunities for developing tough bioadhesive surgical sealants are highlighted.

Nano-porous anodic alumina: fundamentals and applications in tissue engineering.

Recently, nanomaterials have been widely utilized in tissue engineering applications due to their unique properties such as the high surface to volume ratio and diversity of morphology and structure. However, most methods used for the fabrication of nanomaterials are rather complicated and costly. Among different nanomaterials, anodic aluminum oxide (AAO) is a great example of nanoporous structures that can easily be engineered by changing the electrolyte type, anodizing potential, current density, temperature, acid concentration and anodizing time. Nanoporous anodic alumina has often been used for mammalian cell culture, biofunctionalization, drug delivery, and biosensing by coating its surface with biocompatible materials. Despite its wide application in tissue engineering, thorough in vivo and in vitro studies of AAO are still required to enhance its biocompatibility and thereby pave the way for its application in tissue replacements. Recognizing this gap, this review article aims to highlight the biomedical potentials of AAO for applications in tissue replacements along with the mechanism of porous structure formation and pore characteristics in terms of fabrication parameters.

Graphene-Coated Spandex Sensors Embedded into Silicone Sheath for Composites Health Monitoring and Wearable Applications.

This study presents a low-cost, tunable, and stretchable sensor fabricated based on spandex (SpX) yarns coated with graphene nanoplatelets (GnP) through a dip-coating process. The SpX/GnP is wrapped into a stretchable silicone rubber (SR) sheath to protect the conductive layer against harsh conditions, which allows for fabricating washable wearable sensors. Dip-coating parameters are optimized to obtain the maximum GnP coating rate. The covering sheath is tailored to achieve high stretchability beyond the sensing limit of 104% for SpX/GnP/SR sensors. Adjustable sensitivity is attained by manipulating SpX immersion times broadening its application for a wide range of strains: Gauge factors as high as two orders of magnitude are achieved at tensile strains greater than ≈40%. The fabricated sensors are tested for two applications: First, the SpX/GnP sensors are integrated into composite fabrics (with no negative impact on the structural integrity of the part) for screening the yarn displacements, resin flow, solidification during the hot press forming process, and structural health monitoring under mechanical loads with minimal cross-sensitivity to temperature/humidity. Second, the capability of SpX/GnP/SP sensors in detection of a wide range of bodily motions (from the joint motion to arterial blood pressure) is demonstrated.

Poly-Catecholic Functionalization of Biomolecules for Rapid Gelation, Robust Injectable Bioadhesion, and Near-Infrared Responsiveness.

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 NaIO4 solutions 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.

Sodium Phytate-Incorporated Gelatin-Silicate Nanoplatelet Composites for Enhanced Cohesion and Hemostatic Function of Shear-Thinning Biomaterials.

Shear-thinning biomaterials (STBs) based on gelatin-silicate nanoplatelets (SNs) are emerging as an alternative to conventional coiling and clipping techniques in the treatment of vascular anomalies. Improvements in the cohesion of STB hydrogels pave the way toward their translational application in minimally invasive therapies such as endovascular embolization repair. In the present study, sodium phytate (Phyt) additives are used to tune the electrostatic network of SNs-gelatin STBs, thereby promoting their mechanical integrity and facilitating injectability through standard catheters. We show that an optimized amount of Phyt enhances storage modulus by approximately one order of magnitude and reduces injection force by ≈58% without compromising biocompatibility and hydrogel wet stability. The Phyt additives are found to decrease the immune responses induced by SNs. In vitro embolization experiments suggest a significantly lower rate of failure in Phyt-incorporated STBs than in control groups. Furthermore, the addition of Phyt leads to accelerated blood coagulation (reduces clotting time by ≈45% compared to controls) due to the contributions of negatively charged phosphate groups, which aid in the prolonged durability of STB in coagulopathic patients. Therefore, the proposed approach is an effective method for the design of robust and injectable STBs for minimally invasive treatment of vascular malformations.

Template-Enabled Biofabrication of Thick 3D Tissues with Patterned Perfusable Macrochannels.

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.

Thermoresponsive and Injectable Hydrogel for Tissue Agnostic Regeneration.

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.

Stretchable and Bioadhesive Gelatin Methacryloyl-Based Hydrogels Enabled by in Situ Dopamine Polymerization.

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/m3 toughness, 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, versus 2-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 vitro cytocompatibility demonstrated its potential for use in skin-attachable substrates.

Additively Manufactured Gradient Porous Ti-6Al-4V Hip Replacement Implants Embedded with Cell-Laden Gelatin Methacryloyl Hydrogels.

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 vitro biocompatibility 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.

Sacrificial 3D printing of shrinkable silicone elastomers for enhanced feature resolution in flexible tissue scaffolds.

Silicone implants and scaffolds are emerging as potential replacement of flexible tissues, cosmetic and biomedical device implants due to their bioinert and flexible characteristics. The state-of-the-art direct-write silicone three-dimensional (3D) printers however cannot easily 3D print structures with sub-millimeter dimensions because of high viscosity and long curing times of their prepolymers. In the present study, a template-assisted 3D printing of ordered porous silicone constructs is demonstrated. The sacrificial molds were fabricated by low-cost and well-accessible material extrusion 3D printers. The 3D printed molds represent interconnected tortuous high specific surface area porous architectures based on triply periodic minimal surfaces (TPMS) in which the silicone prepolymer is cast and cured. We engineered silicone prepolymer with additives allowing on-demand structural shrinkage upon solvent treatment. This enabled 3D printing at a larger scale compatible with extrusion 3D printer resolution followed by isotropic shrinkage. This procedure led to a volumetric shrinkage of up to ~70% in a highly controllable manner. In this way, pore sizes in the order of 500-600 µm were obtained. The porous constructs were characterized with full strain recovery under extreme compressive deformations of up to 85% of the initial scaffold length. We further demonstrated the ability to infill cell-laden hydrogels such as gelatin methacryloyl (GelMA) into the interconnected pores while maintaining the cell viability of ~90%.

3D-Printed Ultra-Robust Surface-Doped Porous Silicone Sensors for Wearable Biomonitoring.

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.