Broad-spectrum antiviral activity of Spatholobus suberectus Dunn against SARS-CoV-2, SARS-CoV-1, H5N1, and other enveloped viruses.

The current COVID-19 pandemic caused by SARS-Cov-2 is responsible for more than 6 million deaths globally. The development of broad-spectrum and cost-effective antivirals is urgently needed. Medicinal plants are renowned as a complementary approach in which antiviral natural products have been established as safe and effective drugs. Here, we report that the percolation extract of Spatholobus suberectus Dunn (SSP) is a broad-spectrum viral entry inhibitor against SARS-CoV-1/2 and other enveloped viruses. The viral inhibitory activities of the SSP were evaluated by using pseudotyped SARS-CoV-1 and 2, HIV-1ADA and HXB2 , and H5N1. SSP effectively inhibited viral entry and with EC50 values ranging from 3.6 to 5.1 µg/ml. Pre-treatment of pseudovirus or target cells with SSP showed consistent inhibitory activities with the respective EC50 value of 2.3 or 2.1 µg/ml. SSP blocked both SARS-CoV-2 spike glycoprotein and the host ACE2 receptor. In vivo studies indicated that there was no abnormal toxicity and behavior in long-term SSP treatment. Based on these findings, we concluded that SSP has the potential to be developed as a drug candidate for preventing and treating COVID-19 and other emerging enveloped viruses.

Architecture design and advanced manufacturing of heart-on-a-chip: scaffolds, stimulation and sensors.

Heart-on-a-chip (HoC) has emerged as a highly efficient, cost-effective device for the development of engineered cardiac tissue, facilitating high-throughput testing in drug development and clinical treatment. HoC is primarily used to create a biomimetic microphysiological environment conducive to fostering the maturation of cardiac tissue and to gather information regarding the real-time condition of cardiac tissue. The development of architectural design and advanced manufacturing for these "3S" components, scaffolds, stimulation, and sensors is essential for improving the maturity of cardiac tissue cultivated on-chip, as well as the precision and accuracy of tissue states. In this review, the typical structures and manufacturing technologies of the "3S" components are summarized. The design and manufacturing suggestions for each component are proposed. Furthermore, key challenges and future perspectives of HoC platforms with integrated "3S" components are discussed. Architecture design concepts of scaffolds, stimulation and sensors in chips.

Comparison of the Biomechanical Properties between Healthy and Whole Human and Porcine Stomachs.

Gastric cancer poses a societal and economic burden, prompting an exploration into the development of materials suitable for gastric reconstruction. However, there is a dearth of studies on the mechanical properties of porcine and human stomachs. Therefore, this study was conducted to elucidate their mechanical properties, focusing on interspecies correlations. Stress relaxation and tensile tests assessed the hyperelastic and viscoelastic characteristics of porcine and human stomachs. The thickness, stress-strain curve, elastic modulus, and stress relaxation were assessed. Porcine stomachs were significantly thicker than human stomachs. The stiffness contrast between porcine and human stomachs was evident. Porcine stomachs demonstrated varying elastic modulus values, with the highest in the longitudinal mucosa layer of the corpus and the lowest in the longitudinal intact layer of the fundus. In human stomachs, the elastic modulus of the longitudinal muscular layer of the antrum was the highest, whereas that of the circumferential muscularis layer of the corpus was the lowest. The degree of stress relaxation was higher in human stomachs than in porcine stomachs. This study comprehensively elucidated the differences between porcine and human stomachs attributable to variations across different regions and tissue layers, providing essential biomechanical support for subsequent studies in this field.

Engineering Cardiac Tissue for Advanced Heart-On-A-Chip Platforms.

Cardiovascular disease is a major cause of mortality worldwide, and current preclinical models including traditional animal models and 2D cell culture models have limitations in replicating human native heart physiology and response to drugs. Heart-on-a-chip (HoC) technology offers a promising solution by combining the advantages of cardiac tissue engineering and microfluidics to create in vitro 3D cardiac models, which can mimic key aspects of human microphysiological systems and provide controllable microenvironments. Herein, recent advances in HoC technologies are introduced, including engineered cardiac microtissue construction in vitro, microfluidic chip fabrication, microenvironmental stimulation, and real-time feedback systems. The development of cardiac tissue engineering methods is focused for 3D microtissue preparation, advanced strategies for HoC fabrication, and current applications of these platforms. Major challenges in HoC fabrication are discussed and the perspective on the potential for these platforms is provided to advance research and clinical applications.

Electrospun Aligned Nanofiber Yarns Constructed Biomimetic M-Type Interface Integrated into Precise Co-Culture System as Muscle-Tendon Junction-on-a-Chip for Drug Development.

The incorporation of engineered muscle-tendon junction (MTJ) with organ-on-a-chip technology provides promising in vitro models for the understanding of cell-cell interaction at the interface between muscle and tendon tissues. However, developing engineered MTJ tissue with biomimetic anatomical interface structure remains challenging, and the precise co-culture of engineered interface tissue is further regarded as a remarkable obstacle. Herein, an interwoven waving approach is presented to develop engineered MTJ tissue with a biomimetic "M-type" interface structure, and further integrated into a precise co-culture microfluidic device for functional MTJ-on-a-chip fabrication. These multiscale MTJ scaffolds based on electrospun nanofiber yarns enabled 3D cellular alignment and differentiation, and the "M-type" structure led to cellular organization and interaction at the interface zone. Crucially, a compartmentalized co-culture system is integrated into an MTJ-on-a-chip device for the precise co-culture of muscle and tendon zones using their medium at the same time. Such an MTJ-on-a-chip device is further served for drug-associated MTJ toxic or protective efficacy investigations. These results highlight that these interwoven nanofibrous scaffolds with biomimetic "M-type" interface are beneficial for engineered MTJ tissue development, and MTJ-on-a-chip with precise co-culture system indicated their promising potential as in vitro musculoskeletal models for drug development and biological mechanism studies.

Logic-Based Strategy for Spatiotemporal Release of Dual Extracellular Vesicles in Osteoarthritis Treatment.

To effectively treat osteoarthritis (OA), the existing inflammation must be reduced before the cartilage damage can be repaired; this cannot be achieved with a single type of extracellular vesicles (EVs). Here, a hydrogel complex with logic-gates function is proposed that can spatiotemporally controlled release two types of EVs: interleukin 10 (IL-10)+ EVs to promote M2 polarization of macrophage, and SRY-box transcription factor 9 (SOX9)+ EVs to increase cartilage matrix synthesis. Following dose-of-action screening, the dual EVs are loaded into a matrix metalloporoteinase 13 (MMP13)-sensitive self-assembled peptide hydrogel (KM13E) and polyethylene glycol diacrylate/gelatin methacryloyl-hydrogel microspheres (PGE), respectively. These materials are mixed to form a "microspheres-in-gel" KM13E@PGE system. In vitro, KM13E@PGE abruptly released IL-10+ EVs after 3 days and slowly released SOX9+ EVs for more than 30 days. In vivo, KM13E@PGE increased the CD206+ M2 macrophage proportion in the synovial tissue and decreased the tumor necrosis factor-α and IL-1ß levels. The aggrecan and SOX9 expressions in the cartilage tissues are significantly elevated following inflammation subsidence. This performance is not achieved using anti-inflammatory or cartilage repair therapy alone. The present study provides an injectable, integrated delivery system with spatiotemporal control release of dual EVs, and may inspire logic-gates strategies for OA treatment.

Strategies for improving the 3D printability of decellularized extracellular matrix bioink.

3D bioprinting is a revolutionary technology capable of replicating native tissue and organ microenvironments by precisely placing cells into 3D structures using bioinks. However, acquiring the ideal bioink to manufacture biomimetic constructs is challenging. A natural extracellular matrix (ECM) is an organ-specific material that provides physical, chemical, biological, and mechanical cues that are hard to mimic using a small number of components. Organ-derived decellularized ECM (dECM) bioink is revolutionary and has optimal biomimetic properties. However, dECM is always "non-printable" owing to its poor mechanical properties. Recent studies have focused on strategies to improve the 3D printability of dECM bioink. In this review, we highlight the decellularization methods and procedures used to produce these bioinks, effective methods to improve their printability, and recent advances in tissue regeneration using dECM-based bioinks. Finally, we discuss the challenges associated with manufacturing dECM bioinks and their potential large-scale applications.

Injectable photocurable Janus hydrogel delivering hiPSC cardiomyocyte-derived exosome for post-heart surgery adhesion reduction.

Postsurgical pericardial adhesions pose increased risks of sequelae, prolonged reoperation time, and reduced visibility in the surgical field. Here, we introduce an injectable Janus hydrogel, which exhibits asymmetric adhesiveness properties after photocrosslinking, sustained delivering induced pluripotent stem cell-derived cardiomyocyte exosomes (iCM-EXOs) for post-heart surgery adhesion reduction. Our findings reveal that iCM-EXOs effectively attenuate oxidative stress in hydrogen peroxide-treated primary cardiomyocytes by inhibiting the activation of the transcription factor nuclear factor erythroid 2-related factor 2. Notably, in rat cardiac postsurgery models, the Janus hydrogels loaded with iCM-EXOs demonstrate dual functionality, acting as antioxidants and antipericardial adhesion agents. These hydrogels effectively protect iCM-EXOs from GATA6+ cavity macrophage clearance by inhibiting the recruitment of macrophages from the thoracic cavity. These results highlight the promising potential of iCM-EXO-laden Janus hydrogels for clinical safety and efficacy validation in trials involving heart surgery patients, with the ultimate goal of routine administration during open-heart surgeries.

A modular hydrogel bioink containing microsphere-embedded chondrocytes for 3D-printed multiscale composite scaffolds for cartilage repair.

Articular cartilage tissue engineering is being considered an alternative treatment strategy for promoting cartilage damage repair. Herein, we proposed a modular hydrogel-based bioink containing microsphere-embedded chondrocytes for 3D printing multiscale scaffolds integrating the micro and macro environment of the native articular cartilage. Gelatin methacryloyl (GelMA)/alginate microsphere was prepared by a microfluidic approach, and the chondrocytes embedded in the microspheres remained viable after being frozen and resuscitated. The modular hydrogel bioink could be printed via the gel-in-gel 3D bioprinting strategy for fabricating the multiscale hydrogel-based scaffolds. Meanwhile, the cells cultured in the scaffolds showed good proliferation and differentiation. Furthermore, we also found that the composite hydrogel was biocompatible in vivo. These results indicated that the modular hydrogel-based bioinks containing microsphere-embedded chondrocytes for 3D printing multiscale scaffolds could provide a 3D multiscale environment for enhancing cartilage repairing, which would be encouraging considering the numerous alternative applications in articular cartilage tissue engineering.

Bioprinted anisotropic scaffolds with fast stress relaxation bioink for engineering 3D skeletal muscle and repairing volumetric muscle loss.

Viscoelastic hydrogels can enhance 3D cell migration and proliferation due to the faster stress relaxation promoting the arrangement of the cellular microenvironment. However, most synthetic photocurable hydrogels used as bioink materials for 3D bioprinting are typically elastic. Developing a photocurable hydrogel bioink with fast stress relaxation would be beneficial for 3D bioprinting engineered 3D skeletal muscles in vitro and repairing volumetric muscle loss (VML) in vivo; however, this remains an ongoing challenge. This study aims to develop an interpenetrating network (IPN) hydrogel with tunable stress relaxation using a combination of gelatin methacryloyl (GelMA) and fibrinogen. These IPN hydrogels with faster stress relaxation showed higher 3D cellular proliferation and better differentiation. A 3D anisotropic biomimetic scaffold was further developed via a printing gel-in-gel strategy, where the extrusion printing of cell-laden viscoelastic FG hydrogel within Carbopol supported gel. The 3D engineered skeletal muscle tissue was further developed via 3D aligned myotube formation and contraction. Furthermore, the cell-free 3D printed scaffold was implanted into a rat VML model, and both the short and long-term repair results demonstrated its ability to enhance functional skeletal muscle tissue regeneration. These data suggest that such viscoelastic hydrogel provided a suitable 3D microenvironment for enhancing 3D myogenic differentiation, and the 3D bioprinted anisotropic structure provided a 3D macroenvironment for myotube organization, which indicated the potential in skeletal muscle engineering and VML regeneration. STATEMENT OF SIGNIFICANCE: The development of a viscoelastic 3D aligned biomimetic skeletal muscle scaffold has been focused on skeletal muscle regeneration. However, a credible technique combining viscoelastic hydrogel and printing gel-in-gel strategy for fabricating skeletal muscle tissue was rarely reported. Therefore, in this study, we present an interpenetrating network (IPN) hydrogel with fast stress relaxation for 3D bioprinting engineered skeletal muscle via a printing gel-in-gel strategy. Such IPN hydrogels with tunable fast stress relaxation resulted in high 3D cellular proliferation and adequate differentiation in vitro. Besides, the 3D hydrogel-based scaffolds also enhance functional skeletal muscle regeneration in situ. We believe that this study provides several notable advances in tissue engineering that can be potentially used for skeletal muscle injury treatment in clinical.

Multiscale Anisotropic Scaffold Integrating 3D Printing and Electrospinning Techniques as a Heart-on-a-Chip Platform for Evaluating Drug-Induced Cardiotoxicity.

Cardiac safety assessments are significant in drug discovery, as drug-induced cardiotoxicity (DIC) is the primary cause of drug attrition. Despite heart-on-a-chip (HoC) technology becoming an increasingly popular tool for evaluating DIC, its development remains a challenge owing to the anisotropic cardiac structure of the native myocardium. Herein, an anisotropic multiscale cardiac scaffold is presented via a hybrid biofabrication method by combining 3D printing with electrospinning technology, where the 3D-printed micrometer-scale scaffold frames enable mimicking the interwoven myocardium anatomical structure and the branched-aligned electrospun nanofibers network is able to directionally guide cellular arrangements. The in vitro 3D bioengineered cardiac tissues are then fabricated by encapsulating three-layer multiscale scaffolds within a photocurable methacrylated gelatin hydrogel shell. It is demonstrated that such an anisotropic multiscale structure could contribute to enhancing cardiomyocyte maturation and synchronous beating behavior. More attractively, with the integration of 3D bioengineered cardiac tissues and a self-designed microfluidic perfusion system, a 3D anisotropic HoC platform is established for evaluating DIC and cardioprotective efficacy. Collectively, these results indicate that the HoC model developed by integrating the 3D bioengineered cardiac tissues could effectively recapitulate the clinical manifestations, thereby highlighting their efficacy as a valuable preclinical platform for testing drug efficacy and cardiotoxicity.

Photocurable injectable Janus hydrogel with minimally invasive delivery for all-in-one treatment of gastric perforations and postoperative adhesions.

Background: Surgical sutures for sealing gastric perforations (GP) are associated with severe inflammation and postoperative adhesions. Hydrogel bioadhesives offer a potential alternative for sutureless repair of GP; however, their application in minimally invasive surgery is limited due to their prefabricated patch-form, lacking in situ gelation capability. In this study, we emphasized an all-in-one minimally invasive strategy for sutureless repair of acute GP. Methods: an injectable photocurable Janus hydrogel was synthesized, and their ability to seal GP was performed. A rat GP model was used to verify the wound healing and antiadhesion efficiency of hydrogels, and a rabbit GP model was used to verify their laparoscopic feasibility. A fresh human corpse GP model was further employed to verify the user-friendliness of a minimally invasive deliverable (MID) device. A minipig GP model was utilized to evaluate the all-in-one minimally invasive strategy for the treatment of acute GP. Results: Such injectable Janus hydrogel exhibited asymmetric adhesiveness, where the inner-facing side of the hydrogel displays strong sealing and wound healing abilities for GP, while the outward-facing side prevents postoperative adhesion formation. We further developed a minimally invasive deliverable (MID) device integrating hydrogel-delivery parts and photocrosslinking-gelation parts in a laparoscope system. The precise delivery and rapid fluid-tight sealing process of the injectable Janus hydrogel using the MID device for in situ GP repair were demonstrated in a simulated clinical scenario. The in vivo effectiveness of GP sutureless repair was successfully validated in porcine models, with further exploration of the underlying mechanism. Conclusions: Our findings reveal that the injectable Janus hydrogel offers an all-in-one strategy for sutureless GP repair and concurrent prevention of postoperative adhesion formation by incorporating the MID device in minimally invasive surgery, presenting the significant potential to reduce patient surgical complications.

Neural stem cell-derived exosomes-loaded adhesive hydrogel controlled-release promotes cerebral angiogenesis and neurological function in ischemic stroke.

OBJECTIVE: Ischemic stroke has become one of the leading diseases for international death, which brings burden to the economy and society. Exosomes (Exos) derived following neural stem cells (NSCs) stimulation promote neurogenesis and migration of NSCs. However, Exos themselves are easily to be removed in vivo. Our study is to investigate whether adhesive hyaluronic acid (HAD) hydrogel loading NSCs-derived-Exo (HAD-Exo) would promote the recovery of ischemic stroke. METHODS: A mouse model of middle cerebral artery occlusion (MCAO) was established. PBS, Exo, HAD, and HAD-Exo groups were independently stereotactically injected in mice, respectively. The modified neurological severity score scale and behaviour tests were used to evaluate neurological improvement. Neuroimagings were used to observe the improvement of cerebral infarct volume and vessels. Immunofluorescence staining was used to verify the expression of vascular and cell proliferation-related proteins. RESULTS: The structural and mechanical property of HAD and HAD-Exo were detected. Behavioral results showed that HAD-Exo significantly improved neurological functions, especially motor function. Neuroimagings showed that HAD-Exo significantly promoted infarct volume and angiogenesis. Immunofluorescence staining showed that HAD-Exo significantly promoted the cerebral angiogenesis and anti-inflammation. CONCLUSION: NSCs derived exosomes-loaded adhesive HAD hydrogel controlled-release could promote cerebral angiogenesis and neurological function for ischemic stroke.

Electrospun aligned poly(ε-caprolactone) nanofiber yarns guiding 3D organization of tendon stem/progenitor cells in tenogenic differentiation and tendon repair.

Hierarchical anisotropy structure directing 3D cellular orientation plays a crucial role in designing tendon tissue engineering scaffolds. Despite recent development of fabrication technologies for controlling cellular organization and design of scaffolds that mimic the anisotropic structure of native tendon tissue, improvement of tenogenic differentiation remains challenging. Herein, we present 3D aligned poly (ε-caprolactone) nanofiber yarns (NFYs) of varying diameter, fabricated using a dry-wet electrospinning approach, that integrate with nano- and micro-scale structure to mimic the hierarchical structure of collagen fascicles and fibers in native tendon tissue. These aligned NFYs exhibited good in vitro biocompatibility, and their ability to induce 3D cellular alignment and elongation of tendon stem/progenitor cells was demonstrated. Significantly, the aligned NFYs with a diameter of 50 µm were able to promote the tenogenic differentiation of tendon stem/progenitor cells due to the integration of aligned nanofibrous structure and suitable yarn diameter. Rat tendon repair results further showed that bundled NFYs encouraged tendon repair in vivo by inducing neo-collagen organization and orientation. These data suggest that electrospun bundled NFYs formed by aligned nanofibers can mimic the aligned hierarchical structure of native tendon tissue, highlighting their potential as a biomimetic multi-scale scaffold for tendon tissue regeneration.

Injectable remote magnetic nanofiber/hydrogel multiscale scaffold for functional anisotropic skeletal muscle regeneration.

Developing an injectable anisotropic scaffold with precisely topographic cues to induce 3D cellular organization plays a critical role in volumetric muscle loss (VML) repair in vivo. However, controlling aligned myofiber regeneration in vivo based on previous injectable scaffolds continues to prove challenging, especially in a 3D configuration. Herein, we prepare the monodisperse remote magnetic controlled short nanofibers (MSNFs) with a high yield using an advanced coaxial electrospinning-cyrocutting method. An injectable anisotropic MSNF/Gel nanofiber/hydrogel scaffold based on MSNFs within photocurable hydrogel is further designed, showing the ability to guide 3D cellular alignment and organization by the precise microarchitecture control via a remote magnetic field. MSNF/Gel anisotropic scaffolds were able to recreate the macroscale and microscale topographical features of orbicular muscle and bipennate muscle mimicking their anatomical locations. Furthermore, the resultant MSNF/Gel anisotropic scaffolds significantly enhanced aligned myofiber formation in vivo and improved functional recovery of injured muscles in animal VML models. In summary, this approach offers a new promising tissue engineering strategy not only for the aligned myofiber formation for enhancing skeletal muscle regeneration in vivo but also for other biofabrication of living constructs containing complex anisotropy in vitro.

Fabrication of Tß4-Exosome-releasing artificial stem cells for myocardial infarction therapy by improving coronary collateralization.

Currently, stem cell transplantations in cardiac repair are limited owing to disadvantages, such as immunological rejection and poor cell viability. Although direct injection of exosomes can have a curative effect similar to that of stem cell transplantation, high clearance hinders its application in clinical practice. Previous reports suggested that induction of coronary collateralization can be a desired method of adjunctive therapy for someone who had missed the optimal operation time to attenuate myocardial ischemia. In this study, to mimic the paracrine and biological activity of stem cells, we developed artificial stem cells that can continuously release Tß4-exosomes (Tß4-ASCs) by encapsulating specific exosomes within microspheres using microfluidics technology. The results show that Tß4-ASCs can greatly promote coronary collateralization in the periphery of the myocardial infarcted area, and its therapeutic effect is superior to that of directly injecting the exosomes. In addition, to better understand how it works, we demonstrated that the Tß4-ASC-derived exosomes can enhance the angiogenic capacity of coronary endothelial cells (CAECs) via the miR-17-5p/PHD3/Hif-1α pathway. In brief, as artificial stem cells, Tß4-ASCs can constantly release functional exosomes and stimulate the formation of collateral circulation after myocardial infarction, providing a feasible and alternative method for clinical revascularization.

3D-printed high-density polyethylene scaffolds with bioactive and antibacterial layer-by-layer modification for auricle reconstruction.

High-density polyethylene (HDPE) is a promising material for the development of scaffold implants for auricle reconstruction. However, preparing a personalized HDPE auricle implant with favorable bioactive and antibacterial functions to promote skin tissue ingrowth is challenging. Herein, we present 3D-printed HDPE auricle scaffolds with satisfactory pore size and connectivity. The layer-by-layer (LBL) approach was applied to achieve the improved bioactive and antibacterial properties of these 3D printed scaffolds. The HDPE auricle scaffolds were fabricated using an extrusion 3D printing approach, and the individualized macrostructure and porous microstructure were both adjusted by the 3D printing parameters. The polydopamine (pDA) coating method was used to construct a multilayer ε-polylysine (EPL) and fibrin (FIB) modification on the surface of the 3D HDPE scaffold via the LBL self-assembly approach, which provides the bioactive and antibacterial properties. The results of the in vivo experiments using an animal model showed that LBL-coated HDPE auricular scaffolds were able to significantly enhance skin tissue ingrowth and ameliorate the inflammatory response caused by local stress. The results of this study suggest that the combination of the 3D printing technique and surface modification provides a promising strategy for developing personalized implants with biofunctional coatings, which show great potential as a scaffold implant for auricle reconstruction applications.

Injectable composite hydrogels encapsulating gelatin methacryloyl/chitosan microspheres as ARPE-19 cell transplantation carriers.

Retinal pigment epithelial (RPE) cell transplantation is being explored as a feasible approach for treating age-related macular degeneration. The low aggregation ability of RPE cell suspensions or microtissues after transplantation has limited cell utilisation. Therefore, alternative transplantation strategies should be explored to induce cell aggregation and maintain cell viability. Herein, we propose a composite hydrogel that encapsulates gelatin methacryloyl (GelMA)/chitosan microspheres (GCMSs) as ARPE-19 cell transplantation carriers. The diameter of the GCMS was adjusted by tuning the parameters of the microfluidic devices, yielding a cell-adhering platform that induced uniform cell spreading. The live/dead assay and immunofluorescence results showed that ARPE-19 cells adhered and spread uniformly around the microspheres. Moreover, the hydrogel sheets were used to provide an aggregated protective shell, and the ARPE-19 cells on the microspheres encapsulated within these hydrogel sheets remained viable post-injection and produced fewer reactive oxygen species after cyclic stretching. Furthermore, we found that the composite hydrogel was biodegradable and biocompatible in vivo. Therefore, GCMSs provide an injectable microcarrier for ARPE-19 cells, and the hydrogel provides an aggregated protective shell in this novel platform, which has considerable potential for an alternative injectable and highly aggregated RPE cell transplantation strategy design.

3D bioprinting in cardiac tissue engineering.

Heart disease is the main cause of death worldwide. Because death of the myocardium is irreversible, it remains a significant clinical challenge to rescue myocardial deficiency. Cardiac tissue engineering (CTE) is a promising strategy for repairing heart defects and offers platforms for studying cardiac tissue. Numerous achievements have been made in CTE in the past decades based on various advanced engineering approaches. 3D bioprinting has attracted much attention due to its ability to integrate multiple cells within printed scaffolds with complex 3D structures, and many advancements in bioprinted CTE have been reported recently. Herein, we review the recent progress in 3D bioprinting for CTE. After a brief overview of CTE with conventional methods, the current 3D printing strategies are discussed. Bioink formulations based on various biomaterials are introduced, and strategies utilizing composite bioinks are further discussed. Moreover, several applications including heart patches, tissue-engineered cardiac muscle, and other bionic structures created via 3D bioprinting are summarized. Finally, we discuss several crucial challenges and present our perspective on 3D bioprinting techniques in the field of CTE.

Shape Optimization of Costal Cartilage Framework Fabrication Based on Finite Element Analysis for Reducing Incidence of Auricular Reconstruction Complications.

Skin necrosis is the most common complication in total auricular reconstruction, which is mainly induced by vascular compromise and local stress concentration of the overlying skin. Previous studies generally emphasized the increase in the skin flap blood supply, while few reports considered the mechanical factors. However, skin injury is inevitable due to uneasily altered loads generated by the intraoperative continuous negative suction and uneven cartilage framework structure. Herein, this study aims to attain the stable design protocol of the ear cartilage framework to decrease mechanical damage and the incidence of skin necrosis. Finite element analysis was initially utilized to simulate the reconstructive process while the shape optimization technique was then adopted to optimize the three-pretested shape of the hollows inside the scapha and fossa triangularis under negative suction pressure. Finally, the optimal results would be output automatically to meet clinical requirement. Guided by the results of FE-based shape optimization, the optimum framework with the smallest holes inside the scapha and fossa triangularis was derived. Subsequent finite element analysis results also demonstrated the displacement and stress of the post-optimized model were declined 64.9 and 40.1%, respectively. The following clinical study was performed to reveal that this new design reported lower rates of skin necrosis decrease to 5.08%, as well as the cartilage disclosure decreased sharply from 14.2 to 3.39% compared to the conventional method. Both the biomechanical analysis and the clinical study confirmed that the novel design framework could effectively reduce the rates of skin necrosis, which shows important clinical significance for protecting against skin necrosis.