Additive manufacturing, otherwise known as three-dimensional (3D) printing, is driving major innovations in many areas, such as engineering, manufacturing, art, education and medicine. Recent advances have enabled 3D printing of biocompatible materials, cells and supporting components into complex 3D functional living tissues. 3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. Compared with non-biological printing, 3D bioprinting involves additional complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical challenges related to the sensitivities of living cells and the construction of tissues. Addressing these complexities requires the integration of technologies from the fields of engineering, biomaterials science, cell biology, physics and medicine. 3D bioprinting has already been used for the generation and transplantation of several tissues, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. Other applications include developing high-throughput 3D-bioprinted tissue models for research, drug discovery and toxicology.

3D bioprinting of tissues and organs

Additive manufacturing (AM) alias 3D printing translates computer-aided design (CAD) virtual 3D models into physical objects. By digital slicing of CAD, 3D scan, or tomography data, AM builds objects layer by layer without the need for molds or machining. AM enables decentralized fabrication of customized objects on demand by exploiting digital information storage and retrieval via the Internet. The ongoing transition from rapid prototyping to rapid manufacturing prompts new challenges for mechanical engineers and materials scientists alike. Because polymers are by far the most utilized class of materials for AM, this Review focuses on polymer processing and the development of polymers and advanced polymer systems specifically for AM. AM techniques covered include vat photopolymerization (stereolithography), powder bed fusion (SLS), material and binder jetting (inkjet and aerosol 3D printing), sheet lamination (LOM), extrusion (FDM, 3D dispensing, 3D fiber deposition, and 3D plotting), and 3D bioprinting....

Polymers for 3D Printing and Customized Additive Manufacturing

A challenge for tissue engineering is producing three-dimensional (3D), vascularized cellular constructs of clinically relevant size, shape and structural integrity. We present an integrated tissue-organ printer (ITOP) that can fabricate stable, human-scale tissue constructs of any shape. Mechanical stability is achieved by printing cell-laden hydrogels together with biodegradable polymers in integrated patterns and anchored on sacrificial hydrogels. The correct shape of the tissue construct is achieved by representing clinical imaging data as a computer model of the anatomical defect and translating the model into a program that controls the motions of the printer nozzles, which dispense cells to discrete locations. The incorporation of microchannels into the tissue constructs facilitates diffusion of nutrients to printed cells, thereby overcoming the diffusion limit of 100-200 μm for cell survival in engineered tissues. We demonstrate capabilities of the ITOP by fabricating mandible and calvarial bone, cartilage and skeletal muscle. Future development of the ITOP is being directed to the production of tissues for human applications and to the building of more complex tissues and solid organs.

A 3D bioprinting system to produce human-scale tissue constructs with structural integrity

http://www.tissueeng.net/lab/papers/1-s2.0-S014296121500719X-main.pdf

Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels

We demonstrate the additive manufacturing of complex three-dimensional (3D) biological structures using soft protein and polysaccharide hydrogels that are challenging or impossible to create using traditional fabrication approaches. These structures are built by embedding the printed hydrogel within a secondary hydrogel that serves as a temporary, thermoreversible, and biocompatible support. This process, termed freeform reversible embedding of suspended hydrogels, enables 3D printing of hydrated materials with an elastic modulus <500 kPa including alginate, collagen, and fibrin. Computer-aided design models of 3D optical, computed tomography, and magnetic resonance imaging data were 3D printed at a resolution of ~200 μm and at low cost by leveraging open-source hardware and software tools. Proof-of-concept structures based on femurs, branched coronary arteries, trabeculated embryonic hearts, and human brains were mechanically robust and recreated complex 3D internal and external anatomical architectures.

Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels.

A transformation of the healthcare industry is necessary and imminent: hospital-centered, reactive care will soon give way to proactive, person-centered care which focuses on individuals' well-being. However, this transition will only be made possible through scientific innovation. Next-generation technologies will be the key to developing affordable and accessible care, while also lowering the costs of healthcare. A promising solution to this challenge is low-cost continuous health monitoring; this approach allows for effective screening, analysis, and diagnosis and facilitates proactive medical intervention. Urine has great promise for being a key resource for health monitoring; unlike blood, it can be collected effortlessly on a daily basis without pain or the need for special equipment. Unfortunately, the commercial rapid urine analysis tests that exist today can only go so far—this is where the promise of microfluidic devices lies. Microfluidic devices have a proven record of being effective analytical devices, capable of controlling the flow of fluid samples, containing reaction and detection zones, and displaying results, all within a compact footprint. Moving past traditional glass- and polymer-based microfluidics, paper-based microfluidic devices possess the same diagnostic ability, with the added benefits of facile manufacturing, low-cost implementation, and disposability. Hence, we review the recent progress in the application of paper-based microfluidics to urine analysis as a solution to providing continuous health monitoring for proactive care. First, we present important considerations for point-of-care diagnostic devices. We then discuss what urine is and how paper functions as the substrate for urine analysis. Next, we cover the current commercial rapid tests that exist and thereby demonstrate where paper-based microfluidic urine analysis devices may fit into the commercial market in the future. Afterward, we discuss various fabrication techniques that have been recently developed for paper-based microfluidic devices. Transitioning from fabrication to implementation, we present some of the clinically implemented urine assays and their importance in healthcare and clinical diagnosis, with a focus on paper-based microfluidic assays. We then conclude by providing an overview of select biomarker research tailored towards urine diagnostics. This review will demonstrate the applicability of paper-based assays for urine analysis and where they may fit into the commercial healthcare market.

/pdf/paper-based-assays-for-urine-analysis-3i6mgygk1a.pdf

Paper-based assays for urine analysis.

Paper-based micro analytical devices offer significant advantages compared to the conventional microfluidic chips including cost-effectiveness, ease of fabrication, and ease of use while preserving critical features including strong capillary action and biological compatibility. In this work, we demonstrate an inexpensive, rapid method for high-throughput fabrication of paper-based microfluidics by patterning hydrophobic barriers using a desktop pen plotter integrated with a custom-made, low-cost paper feeder. We tested various types of commercial permanent markers and compared their water-resistant capabilities for creating hydrophobic barriers. Additionally, we studied the performance of markers with different types of paper, plotting speeds, and pattern dimensions. To verify the effectiveness of the presented fabrication method, colorimetric analysis was performed on the results of a glucose assay.

High-throughput rapid-prototyping of low-cost paper-based microfluidics

There is an urgent for a novel approach to cancer research with 1.7 million new cases of cancer occurring every year in the United States of America. Tumor models offer promise as a useful platform for cancer research without the need for animal models, but there remains a challenge to fabricate a relevant model which mimics the structure, function and drug response of human tumors. Bioprinting can address this need by fabricating three-dimensional constructs that mimic tumor heterogeneity, vasculature and spheroid structures. Furthermore, bioprinting can be used to fabricate tissue constructs within microfluidic platforms, forming tumor-on-a-chip devices which are ideal for high-throughput testing in a biomimetic microenvironment. Applications of tumors-on-a-chip include facilitating basic research to better understand tumor development, structure and function as well as drug screening to improve the efficiency of cancer drug discovery.

http://ijb.whioce.com/index.php/int-j-bioprinting/article/download/77/pdf_23

Advancing cancer research using bioprinting for tumor-on-a-chip platforms

In nature, cells adhere and detach selectively in circulation with sophisticated signaling mechanisms.[1–4] Selective capture of cells and biological materials using microfluidics has been a rapidly growing field with multiple applications in diagnostics (e.g., CD4 cell count for HIV monitoring,[5–9] capture of circulating tumor cells,[10] pathogen detection,[11–13] isolation of neutrophils from blood,[14] isolation of mixed leucocytes,[15] and separation of T-lymphocytes[16]) and regenerative medicine for stem cell isolation.[17,18] Microfluidic devices offer advantages such as handling small samples volumes, low consumption of expensive reagents, and shorter assay times, enabling portable automated devices.[7,9,17] Although capturing cells in micro-channels has been studied, spatial control of capture and on-demand release of cells in microfluidic channels remains as an unaddressed challenge.

/pdf/smart-interface-materials-integrated-with-microfluidics-for-4z8zgcwqg3.pdf

Smart Interface Materials Integrated with Microfluidics for On-Demand Local Capture and Release of Cells

Recent technological advancements have made strides in shifting clinical diagnostics from large centralized laboratories to the point of care, thus widely increasing the accessibility to such diagnostic procedures worldwide. For sickle cell disease diagnostics, many current technologies require costly equipment and specialized training while others rely on subjective interpretation of results and can be vulnerable to user error. In contrast, the self-contained, user-friendly, and low-cost platform proposed here uses magnetic focusing to separate, image, and analyze blood cells based on their densities. Here, the applicability of this approach is demonstrated to provide a quantitative diagnosis of sickle cell disease. Further, in low-resource settings such as sub-Saharan Africa (where the disease is common but no ubiquitous testing and monitoring procedures are in place), this technology can enable simple, rapid, and accessible sickle cell disease diagnostics and monitoring.

Savas Tasoglu

Papers

Paper-based assays for urine analysis.

High-throughput rapid-prototyping of low-cost paper-based microfluidics

Advancing cancer research using bioprinting for tumor-on-a-chip platforms

Smart Interface Materials Integrated with Microfluidics for On-Demand Local Capture and Release of Cells

Label-Free Sickle Cell Disease Diagnosis using a Low-Cost, Handheld Platform