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Current xenograft animal models fail to accurately replicate the complexity of human bone disease. To gain translatable and clinically valuable data from animal models, new in vivo models need to be developed that mimic pivotal aspects of human bone physiology as well as its diseased state. Above all, an advanced bone disease model should promote the development of new treatment strategies and facilitate the conduction of common clinical interventional procedures. Here we describe the development and characterisation of an orthotopic humanised tissue-engineered osteosarcoma (OS) model in a recently genetically engineered x-linked severe combined immunodeficient (X-SCID) rat. For the first time in a genetically modified rat, our results show the successful implementation of an orthotopic humanised tissue-engineered bone niche supporting the growth of a human OS cell line including its metastatic spread to the lung. Moreover, we studied the inter- and intraspecies differences in ultrastructural composition of bone and calcified tissue produced by the tumour, pointing to the crucial role of humanised animal models.

Heart valve tissue engineering (HVTE) aims to provide living autologous heart valve implants endowed with regenerative capabilities and life-long durability. However, fabrication of biomimetic scaffolds capable of providing the required functionality in terms of mechanical performance and tunable porosity to enable cellular infiltration remains a major challenge. Here, the additive manufacturing of bioinspired, spatially heterogeneous, tubular scaffolds enclosing the leaflets, inter-leaflet triangles, and their interface for in situ HVTE using melt electrowriting (MEW) is demonstrated. The innovative platform enables the digital fabrication of scaffolds with ad hoc architecture (e.g., tunable location, specific fiber pattern, and orientation) and customizable geometry via a custom-made control software. The user-friendly interface allows for the definition of areas of the scaffold with specific patterns to obtain properties such as tunable J-shaped stress–stain curve and anisotropy typical of the heart valve leaflet, compliant inter-leaflet triangles, and reinforced curvilinear boundary between them. Heterogeneous, tubular, heart valve MEW scaffolds are then embedded with a microporous elastin-like recombinamer (ELR) hydrogel to develop a soft-network composite favoring cell infiltration and ensuring hemocompatibility. The acute systolic hemodynamic functionality of the MEW/ELR composite satisfies the ISO 5840 requirements, under aortic and pulmonary conditions.

Described as a projection (prolapse) of tissue through a fascial defect in the abdominal wall, hernias are associated with significant rates of complications, recurrence, and reoperations. This literature review is aimed at providing an overview of the prosthetic surgical meshes used for the repairing of hernia defects. The review was carried out using two specialized online databases: Espacenet, from the European Patent Office (EPO), and WIPO from the World Intellectual Property Organization. Of the 56 patents selected from 2008 to 2018, China was the largest contributor with 55% (31 patents) of the total patent applicant filings, followed by the United States of America (US), with 29% (16 patents). Although the majority of patent applications (39 documents) had at least one company (industry) assigned to the patent application, 4 patents were solely from academic research. Our data showed that only 13 industry applicants have had their products included in the market, and the majority of meshes available on the market are still made from polypropylene. Chemical, physical, and mesh surface modifications have been implemented, and a few reviews describing mesh design, composition, and mechanical properties are available. However, to date, the ideal mesh implant from a clinical point of view has not been developed.

The quest for an advanced soft robotic actuator technology that is fast and can execute a wide range of application-specific tasks at multiple length scales is still ongoing. Here, we demonstrate a new design and manufacturing strategy that leads to high-speed inflatable actuators exhibiting diverse movements. Our approach leverages the concept of miniaturisation to reduce the required volume of fluid for actuation as well as fibre-reinforcement to improve the efficiency of actuators in converting delivered fluids into fast and predictable movement. To fabricate the designs, we employ a class of additive manufacturing technology called melt electrowriting. We demonstrate 3D printing of microfibre architectures on soft elastomers with precision at unprecedently small length scales, leading to miniaturised composite actuators with highly controlled deformation characteristics. We show that owing to their small dimensions and deterministically designed fibrous networks, our actuators require extremely low amounts of fluid to inflate. We demonstrate that actuators with a length of 10-15 mm and an inner diameter 1 mm can reach their full range of motion within ∼20 ms without exploiting snapping instabilities or material non-linearities. We display the speed of our actuators by building an ultrafast, soft flycatcher. We also show that our actuators outperform their counterparts with respect to achievable movement diversity and complexity.

Reconstructive surgery aims to restore tissue defects by replacing them with similar autologous tissue to achieve good clinical outcomes. However, often the defect is too large or the tissue available is limited, requiring synthetic materials to restore the anatomical shape and partial function. The utilization of three-dimensional (3D) printing allows for the manufacture of implants with complex geometries and internal architecture that more closely matches the required clinical needs. Synthetic polymers offer certain advantages over natural polymers as biomedical materials due to their ability to more closely mimic the mechanical and chemical properties of the native tissue. Synthetic polymer materials such as poly(lactic acid) and acrylonitrile butadiene styrene are easily 3D printed to generate 3D objects due to their flexibility in their chemical and mechanical properties and physical form. Polyurethanes (PUs) are widely used as short- and long-term, implantable medical devices due to their good mechanical properties, biocompatibility, and hemocompatibility. This article provides an overview on the advancement of 3D printable PU-based materials for biomedical applications. A summary of the chemical structure and synthesis of PUs is provided to explain how PUs may be processed into medical devices using additive manufacturing techniques. Currently, PUs are being explored by several 3D printing approaches, including fused filament fabrication, bioplotting, and stereolithography, to fabricate complex implants with precise patterns and shapes with fine resolution. PU scaffolds using 3D printing have shown good cell viability and tissue integration in vivo. The important limitations of PU printing are identified to stimulate future research. PUs offer a biocompatible, synthetic polymeric material that can be 3D printed to manufacture implants that are tailored to meet specific anatomical, mechanical, and biological requirements for biomedical applications.

The manufacture of fibrous scaffolds with tailored micrometric features and anatomically relevant three-dimensional (3D) geometries for soft tissue engineering applications remains a great challenge. Melt electrowriting (MEW) is an advanced additive manufacturing technique capable of depositing predefined micrometric fibers. However, it has been so far inherently limited to simple planar and tubular scaffold geometries because of the need to avoid polymer jet instabilities. In this work, we surmount the technical boundaries of MEW to enable the manufacture of complex fibrous scaffolds with simultaneous controlled micrometric and patient-specific anatomic features. As an example of complex geometry, aortic root scaffolds featuring the sinuses of Valsalva were realized. By modeling the electric field strength associated with the MEW process for these constructs, we found that the combination of a conductive core mandrel with a non-conductive 3D printed model reproducing the complex geometry minimized the variability of the electric field thus enabling the accurate deposition of fibers. We validated these findings experimentally and leveraged the micrometric resolution of MEW to fabricate unprecedented fibrous aortic root scaffolds with anatomically relevant shapes and biomimetic microstructures and mechanical properties. Furthermore, we demonstrated the fabrication of patient-specific aortic root constructs from the 3D reconstruction of computed tomography clinical data.

Stereolithography (SL) has several advantages over traditional biomanufacturing techniques such as fused deposition modeling, including increased speed, accuracy, and efficiency. While SL has been broadly used in tissue engineering for the fabrication of three-dimensional scaffolds that can mimic the in vivo environment for cell growth and tissue regeneration, lithographic printing is usually performed on single-component materials cured with ultraviolet light, severely limiting the versatility and cytocompatibility of such systems. In this study, we report a highly tunable, low-cost photoinitiator system that we used to establish a systematic library of crosslinked materials based on low molecular weight poly(ethylene glycol) diacrylate. We assessed the physicochemical properties, photocrosslinking efficiency, cost performance, and biocompatibility to demonstrate the capability of manufacturing a multimaterial complex tissue scaffold. Color images are available online. Stereolithography (SL) has advantages over traditional biomanufacturing techniques, including accuracy and efficiency. While SL has been broadly used for fabricating three-dimensional scaffolds that can mimic the in vivo environment for cell growth and tissue regeneration, lithographic printing is usually performed on single-component materials cured with ultraviolet light, severely limiting the versatility and cytocompatibility of such systems. In this study, we report a highly tunable photoinitiator system and establish a systematic library of crosslinked materials based on poly(ethylene glycol) diacrylate. We assessed the physicochemical properties, photocrosslinking efficiency and biocompatibility to demonstrate the capability of manufacturing a multimaterial complex tissue scaffold.

Heart valves are characterized to be highly flexible yet tough, and exhibit complex deformation characteristics such as nonlinearity, anisotropy, and viscoelasticity, which are, at best, only partially recapitulated in scaffolds for heart valve tissue engineering (HVTE). These biomechanical features are dictated by the structural properties and microarchitecture of the major tissue constituents, in particular collagen fibers. In this study, the unique capabilities of melt electrowriting (MEW) are exploited to create functional scaffolds with highly controlled fibrous microarchitectures mimicking the wavy nature of the collagen fibers and their load‐dependent recruitment. Scaffolds with precisely‐defined serpentine architectures reproduce the J‐shaped strain stiffening, anisotropic and viscoelastic behavior of native heart valve leaflets, as demonstrated by quasistatic and dynamic mechanical characterization. They also support the growth of human vascular smooth muscle cells seeded both directly or encapsulated in fibrin, and promote the deposition of valvular extracellular matrix components. Finally, proof‐of‐principle MEW trileaflet valves display excellent acute hydrodynamic performance under aortic physiological conditions in a custom‐made flow loop. The convergence of MEW and a biomimetic design approach enables a new paradigm for the manufacturing of scaffolds with highly controlled microarchitectures, biocompatibility, and stringent nonlinear and anisotropic mechanical properties required for HVTE.

Three-dimensionally (3D) printed scaffolds and cell culture lattices with microscale features are increasingly being used in tissue engineering and regenerative medicine. One additive manufacturing technology used to design and fabricate such structures is melt electrowriting (MEW), a process which needs to be scaled in production to effectively translate to industrial applications. In this study, a scale-up printer, designed with eight simultaneously extruding heads, is constructed and validated. Importantly, identical structures could be fabricated using parameters developed from a single-head system, therefore establishing a MEW printer ecosystem that allows for direct upscaling from laboratory research. The successful transfer to vertically mounted collectors produced homogeneous reproducible scaffolds with identical morphologies and fiber diameters. These proof-of-concept experiments also show that MEW is capable of large-scale fabrication, successfully demonstrated by manufacturing 780 × 780-mm sheets of scaffolds/lattices. This study demonstrates that upscaling MEW can be realized by multiplying the number of print heads, while vertical mounting of the collector significantly reduces the MEW footprint. Additionally, economic aspects were considered during the development and costly components, such as the x, y, and z linear axes, were minimized. Herein, a systems engineering approach for the development of a high-throughput MEW technology platform is presented for the first time.

Gelatin methacryloyl (GelMA) hydrogels are a mechanically and biochemically tuneable biomaterial, facilitating chondrocyte culture for tissue engineering applications. However, a lack of characterisation and standardisation of fabrication methodologies for GelMA restricts its utilisation in surgical interventions for articular cartilage repair. The purpose of this study was to determine the effects of gelatin source and photoinitiator type on the redifferentiation capacity of monolayer-expanded human articular chondrocytes encapsulated in GelMA/hyaluronic acid methacrylate (HAMA) hydrogels. Chondrocyte-laden hydrogels reinforced with multiphasic melt-electrowritten (MEW) medical grade polycaprolactone (mPCL) microfibre scaffolds were prepared using bovine (B) or porcine-derived (P) GelMA, and photocrosslinked with either lithium acylphosphinate (LAP) and visible light (405 nm) or Irgacure 2959 (IC) and UV light (365 nm). Bulk physical properties, cell viability and biochemical features of hydrogel constructs were measured at day 1 and day 28 of chondrogenic cell culture. The compressive moduli of all groups increased after 28 days of cell culture, with B-IC displaying similar compressive strength to that of native articular cartilage (∼1.5 MPa). Compressive moduli correlated with an increase in total glycosaminoglycan (GAG) content for each group. Gene expression analysis revealed upregulation of chondrogenic marker genes in IC-crosslinked groups, whilst dedifferentiation gene markers were upregulated in LAP-crosslinked groups. mPCL reinforcement correlated with increased accumulation of collagen I and II in B-IC, B-LAP and P-IC groups compared to non-reinforced hydrogels. A reduction in cell viability was noted in all samples at day 28, potentially due to the generation of free radicals during photocrosslinking or cytotoxicity of the photoinitiators. In summary, hydrogel constructs prepared with bovine-derived GelMA and photocrosslinked with Irgacure 2959 and 365 n