3D Printing of Interpenetrating Network Flexible Hydrogels with Enhancement of Adhesiveness.

3D printing of hydrogels has been widely explored for the rapid fabrication of complex soft structures and devices. However, using 3D printing to customize hydrogels with both adequate adhesiveness and toughness remains a fundamental challenge. Here, we demonstrate mussel-inspired (polydopamine) PDA hydrogel through the incorporation of a classical double network (2-acrylamido-2-methylpropanesulfonic acid) PAMPS/(polyacrylamide) PAAm to achieve simultaneously tailored adhesiveness, toughness, and biocompatibility and validate the 3D printability of such a hydrogel into customized architectures. The strategy of combining PDA with PAMPS/PAAm hydrogels leads to favorable adhesion on either hydrophilic or hydrophobic surfaces. The hydrogel also shows excellent flexibility, which is attributed to the reversible cross-linking of PDA and PAMPS, together with the long-chain PAAm cross-linking network. Among them, the reversible cross-linking of PDA and PAMPS is capable of dissipating mechanical energy under deformation. Meanwhile, the long-chain PAAm network contributes to maintaining a high deformation capability. We establish a theoretical framework to quantify the contribution of the interpenetrating networks to the overall toughness of the hydrogel, which also provides guidance for the rational design of materials with the desired properties. Our work manifests a new paradigm of printing adhesive, tough, and biocompatible interpenetrating network hydrogels to meet the requirements of broad potential applications in biomedical engineering, soft robotics, and intelligent and superabsorbent devices.

3D direct printing of mechanical and biocompatible hydrogel meta-structures.

Direct Ink Writing (DIW) has demonstrated great potential as a versatile method to 3D print multifunctional structures. In this work, we report the implementation of hydrogel meta-structures using DIW at room temperature, which seamlessly integrate large specific surface areas, interconnected porous characteristics, mechanical toughness, biocompatibility, and water absorption and retention capabilities. Robust but hydrophobic polymers and weakly crosslinked nature-origin hydrogels form a balance in the self-supporting ink, allowing us to directly print complex meta-structures without sacrificial materials and heating extrusion. Mechanically, the mixed bending or stretching of symmetrical re-entrant cellular lattices and the unique curvature patterns are combined to provide little lateral expansion and large compressive energy absorbance when external forces are applied on the printed meta-structures. In addition, we have successfully demonstrated ear, aortic valve conduits and hierarchical architectures. We anticipate that the reported 3D meta-structured hydrogel would offer a new strategy to develop functional biomaterials for tissue engineering applications in the future.

Antibodies Targeting Two Epitopes in SARS-CoV-2 Neutralize Pseudoviruses with the Spike Proteins from Different Variants.

The COVID-19 pandemic was caused by SARS-CoV-2 infection. To prevent the spread of SARS-CoV-2, an effective vaccine is required. Two linear peptides from potential B-cell epitopes in the spike protein of SARS-CoV-2 (a.a. 440-460; a.a. 494-506) were synthesized and used to immunize rabbits. High-titer antibodies of IgG were produced, purified, and verified by Western blot analysis. Antibodies against these two epitopes could effectively neutralize SARS-CoV-2 pseudoviral particles with the spike proteins from not only the original strain (basal; wild-type), but also a strain with a single point mutation (D614G), and two other emerging variants (the Alpha and Beta variants) prevalent around the world, but not from SARS-CoV. In conclusion, antibodies against these two epitopes are protective. This information is important for the development of vaccines against SARS-CoV-2.

Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy.

During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specifically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα downstream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Furthermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeutic efficiency, providing a novel strategy for RA therapy.

3D bioprinting of vascular conduits for pediatric congenital heart repairs.

In children with congenital heart defects, surgical correction often involves the use of valves, patches or vascular conduits to establish anatomic continuity. Due to the differences between the pediatric and adult populations, tissue reconstruction in pediatric patients requires a substantially different approach from those in adults. Cardiovascular anatomy of children with congenital heart defect vary, which requires tailored surgical operations for each patient. Since grafts used in these palliative surgeries are sensitive to the local hemodynamic environments, their geometries need to be precisely designed to ensure long-term performance. Tissue engineered vascular grafts (TEVGs) have made tremendous progress over the past decade, but it remains difficult to fabricate patient- and operation-specific vascular grafts. This review summarizes historical milestones of TEVG development for repairing pediatric congenital defects and current clinical outcomes. We also highlight ongoing works on 3D bioprinting of TEVGs with complex geometries and address the current limitations of each technique. Although 3D bioprinted vascular grafts with appropriate functions are yet to be developed, some of the current researches are promising to create better patient specific tissue engineered vascular grafts in the future.

Intravenous administration of multipotent stromal cells and bone allograft modification to enhance allograft healing.

Aim: This study investigated a coordinated strategy of revitalizing bone allograft with circulating multipotent stromal cells (MSCs). Materials & methods: After chemotactic and releasing assessments, stromal cell-derived factor 1 and platelet-derived growth factor BB in copolymers were coated on the bone allograft (AlloS-P). Allograft coated with copolymers alone (Allo), as controls, or AlloS-P was implanted into the femur of athymic mice, which received intravenous injections of human MSCs or saline at weeks 1, 2 and 3. Results: At week 8, the total callus volume (both cartilaginous and bony callus) around the allograft was the largest in the AlloS-P + MSC group (p < 0.05). Conclusion: Coating bone allograft with stromal cell-derived factor 1 and platelet-derived growth factor BB and intravenous injections of MSCs improved allograft incorporation.

Highly Elastic Biodegradable Single-Network Hydrogel for Cell Printing.

Cell printing is becoming a common technique to fabricate cellularized printed scaffold for biomedical application. There are still significant challenges in soft tissue bioprinting using hydrogels, which requires live cells inside the hydrogels. Moreover, the resilient mechanical properties from hydrogels are also required to mechanically mimic the native soft tissues. Herein, we developed a visible-light cross-linked, single-network, biodegradable hydrogel with high elasticity and flexibility for cell printing, which is different from previous highly elastic hydrogel with double-network and two components. The single-network hydrogel using only one stimulus (visible light) to trigger gelation can greatly simplify the cell printing process. The obtained hydrogels possessed high elasticity, and their mechanical properties can be tuned to match various native soft tissues. The hydrogels had good cell compatibility to support fibroblast growth in vitro. Various human cells were bioprinted with the hydrogels to form cell-gel constructs, in which the cells exhibited high viability after 7 days of culture. Complex patterns were printed by the hydrogels, suggesting the hydrogel feasibility for cell printing. We believe that this highly elastic, single-network hydrogel can be simply printed with different cell types, and it may provide a new material platform and a new way of thinking for hydrogel-based bioprinting research.

Human Skin Constructs with Spatially Controlled Vasculature Using Primary and iPSC-Derived Endothelial Cells.

Vascularization of engineered human skin constructs is crucial for recapitulation of systemic drug delivery and for their long-term survival, functionality, and viable engraftment. In this study, the latest microfabrication techniques are used and a novel bioengineering approach is established to micropattern spatially controlled and perfusable vascular networks in 3D human skin equivalents using both primary and induced pluripotent stem cell (iPSC)-derived endothelial cells. Using 3D printing technology makes it possible to control the geometry of the micropatterned vascular networks. It is verified that vascularized human skin equivalents (vHSEs) can form a robust epidermis and establish an endothelial barrier function, which allows for the recapitulation of both topical and systemic delivery of drugs. In addition, the therapeutic potential of vHSEs for cutaneous wounds on immunodeficient mice is examined and it is demonstrated that vHSEs can both promote and guide neovascularization during wound healing. Overall, this innovative bioengineering approach can enable in vitro evaluation of topical and systemic drug delivery as well as improve the potential of engineered skin constructs to be used as a potential therapeutic option for the treatment of cutaneous wounds.

The potential and electric field in the cochlear outer hair cell membrane.

Outer hair cell electromechanics, critically important to mammalian active hearing, is driven by the cell membrane potential. The membrane protein prestin is a crucial component of the active outer hair cell's motor. The focus of the paper is the analysis of the local membrane potential and electric field resulting from the interaction of electric charges involved. Here the relevant charges are the ions inside and outside the cell, lipid bilayer charges, and prestin-associated charges (mobile-transferred by the protein under the action of the applied field, and stationary-relatively unmoved by the field). The electric potentials across and along the membrane are computed for the case of an applied DC-field. The local amplitudes and phases of the potential under different frequencies are analyzed for the case of a DC + AC-field. We found that the effect of the system of charges alters the electric potential and internal field, which deviate significantly from their traditional linear and constant distributions. Under DC + AC conditions, the strong frequency dependence of the prestin mobile charge has a relatively small effect on the amplitude and phase of the resulting potential. The obtained results can help in a better understanding and experimental verification of the mechanism of prestin performance.

Challenges and promises in modeling dermatologic disorders with bioengineered skin.

The tremendous cost of drug development is often attributed to the long time interval between identifying lead compounds in preclinical studies to assessing clinical efficacy in randomized clinical trials. Many candidate molecules show promise in cell culture or animal models, only to fail in late stage in human investigations. There is a need for novel technologies that allow investigators to quickly and reliably predict drug safety and efficacy. The advent of microtechnology has made it possible to integrate multiple microphysiologic organ systems into a single microfabricated chip. This review focuses on three-dimensional engineered skin, which has enjoyed a long history of uses both in clinical treatments of refractory ulcers and as a laboratory model. We discuss current biological and engineering challenges in construction of a robust bioengineered skin and provide a blueprint for its potential utility to model dermatologic disorders such as psoriasis or cutaneous drug reactions.