@article{shirwaiker_fisher_anderson_schuchard_warren_maze_grondin_ligler_pourdeyhimi_2020, title={High-Throughput Manufacture of 3D Fiber Scaffolds for Regenerative Medicine}, volume={26}, ISSN={["1937-3392"]}, DOI={10.1089/ten.tec.2020.0098}, abstractNote={Engineered scaffolds used to regenerate mammalian tissues should recapitulate the underlying fibrous architecture of native tissue to achieve comparable function. Current fibrous scaffold fabrication processes, such as electrospinning and three-dimensional (3D) printing, possess application-specific advantages, but they are limited either by achievable fiber sizes and pore resolution, processing efficiency, or architectural control in three dimensions. As such, a gap exists in efficiently producing clinically relevant, anatomically sized scaffolds comprising fibers in the 1–100 μm range that are highly organized. This study introduces a new high-throughput, additive fibrous scaffold fabrication process, designated in this study as 3D melt blowing (3DMB). The 3DMB system described in this study is modified from larger nonwovens manufacturing machinery to accommodate the lower volume, high-cost polymers used for tissue engineering and implantable biomedical devices and has a fiber collection component that uses adaptable robotics to create scaffolds with predetermined geometries. The fundamental process principles, system design, and key parameters are described, and two examples of the capabilities to create scaffolds for biomedical engineering applications are demonstrated. Impact statement Three-dimensional melt blowing (3DMB) is a new, high-throughput, additive manufacturing process to produce scaffolds composed of highly organized fibers in the anatomically relevant 1–100 μm range. Unlike conventional melt-blowing systems, the 3DMB process is configured for efficient use with the relatively expensive polymers necessary for biomedical applications, decreasing the required amounts of material for processing while achieving high throughputs compared with 3D printing or electrospinning. The 3DMB is demonstrated to make scaffolds composed of multiple fiber materials and organized into complex shapes, including those typical of human body parts.}, number={7}, journal={TISSUE ENGINEERING PART C-METHODS}, author={Shirwaiker, Rohan A. and Fisher, Matthew B. and Anderson, Bruce and Schuchard, Karl G. and Warren, Paul B. and Maze, Benoit and Grondin, Pierre and Ligler, Frances S. and Pourdeyhimi, Behnam}, year={2020}, month={Jul}, pages={364–374} }
 @article{huebner_warren_chester_spang_brown_fisher_shirwaiker_2019, title={Mechanical properties of tissue formed in vivo are affected by 3D-bioplotted scaffold microarchitecture and correlate with ECM collagen fiber alignment}, volume={61}, ISSN={0300-8207 1607-8438}, url={http://dx.doi.org/10.1080/03008207.2019.1624733}, DOI={10.1080/03008207.2019.1624733}, abstractNote={ABSTRACT Purpose: Musculoskeletal soft tissues possess highly aligned extracellular collagenous networks that provide structure and strength. Such an organization dictates tissue-specific mechanical properties but can be difficult to replicate by engineered biological substitutes. Nanofibrous electrospun scaffolds have demonstrated the ability to control cell-secreted collagen alignment, but concerns exist regarding their scalability for larger and anatomically relevant applications. Additive manufacturing processes, such as melt extrusion-based 3D-Bioplotting, allow fabrication of structurally relevant scaffolds featuring highly controllable porous microarchitectures. Materials and Methods: In this study, we investigate the effects of 3D-bioplotted scaffold design on the compressive elastic modulus of neotissue formed in vivo in a subcutaneous rat model and its correlation with the alignment of ECM collagen fibers. Polycaprolactone scaffolds featuring either 100 or 400 µm interstrand spacing were implanted for 4 or 12 weeks, harvested, cryosectioned, and characterized using atomic-force-microscopy-based force mapping. Results: The compressive elastic modulus of the neotissue formed within the 100 µm design was significantly higher at 4 weeks (p < 0.05), but no differences were observed at 12 weeks. In general, the tissue stiffness was within the same order of magnitude and range of values measured in native musculoskeletal soft tissues including the porcine meniscus and anterior cruciate ligament. Finally, a significant positive correlation was noted between tissue stiffness and the degree of ECM collagen fiber alignment (p < 0.05) resulting from contact guidance provided by scaffold strands. Conclusion: These findings demonstrate the significant effects of 3D-bioplotted scaffold microarchitectures in the organization and sub-tissue-level mechanical properties of ECM in vivo.}, number={2}, journal={Connective Tissue Research}, publisher={Informa UK Limited}, author={Huebner, Pedro and Warren, Paul B. and Chester, Daniel and Spang, Jeffrey T. and Brown, Ashley C. and Fisher, Matthew B. and Shirwaiker, Rohan A.}, year={2019}, month={Jul}, pages={190–204} }
 @article{warren_davis_fisher_2019, title={Parametric control of fiber morphology and tensile mechanics in scaffolds with high aspect ratio geometry produced via melt electrowriting for musculoskeletal soft tissue engineering}, volume={99}, ISSN={["1878-0180"]}, DOI={10.1016/j.jmbbm.2019.07.013}, abstractNote={Melt electrowriting (MEW) is an additive manufacturing technique that has the potential to create fibrous scaffolds that reproduce the scale and organization of collagen fiber networks in musculoskeletal soft tissues. For musculoskeletal soft tissue engineering, it is useful for scaffolds to have a high aspect ratio (length to width ratio of 5:1 or higher). However, the relationship between MEW process variables and the structural and mechanical properties of such scaffolds is not well understood. In addition, prior studies have cut samples from larger MEW structures, resulting in test specimens with discontinuous fibers. In this study, MEW scaffolds with low (square, 12 mm × 12 mm) and high aspect ratio (rectangular, 35 mm × 5 mm) macroscale geometries were fabricated at varying stage translation speeds or melt extrusion temperatures. Fiber morphology in both geometries and mechanical properties of the continuous rectangular structures were then quantified. Fiber diameter in both square and rectangular scaffolds generally decreased with increasing stage speed, but increased with melt temperature, though the effect of the latter was greater in square scaffolds. Interfiber spacing in both geometries was closer to the intended value as stage speed increased. Spacing became less accurate in square scaffolds with increasing melt temperature but changed little in rectangular scaffolds. Transverse fiber angle in rectangular scaffolds improved with increasing stage speed and had a median value within 1.4% of the intended angle at all temperatures. Finally, apparent tensile modulus in rectangular scaffolds decreased with increasing speed and temperature. These findings highlight the need to tailor MEW process parameters in scaffolds with high aspect ratio geometry in order to consistently generate specific structural and mechanical properties. Because of the potential to reproduce the structural anisotropy, fiber size, and mechanical properties of collagenous extracellular matrix, MEW structures are promising as musculoskeletal soft tissue scaffolds.}, journal={JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS}, author={Warren, Paul B. and Davis, Zachary G. and Fisher, Matthew B.}, year={2019}, month={Nov}, pages={153–160} }
 @article{warren_huebner_spang_shirwaiker_fisher_2017, title={Engineering 3D-Bioplotted scaffolds to induce aligned extracellular matrix deposition for musculoskeletal soft tissue replacement}, volume={58}, ISSN={["1607-8438"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85011664862&partnerID=MN8TOARS}, DOI={10.1080/03008207.2016.1276177}, abstractNote={ABSTRACT Purpose: Tissue engineering and regenerative medicine approaches have the potential to overcome the challenges associated with current treatment strategies for meniscus injuries. 3D-Bioplotted scaffolds are promising, but have not demonstrated the ability to guide the formation of aligned collagenous matrix in vivo, which is critical for generating functional meniscus tissue. In this study, we evaluate the ability of 3D-Bioplotted scaffold designs with varying interstrand spacing to induce the deposition of aligned matrix in vivo. Materials and Methods: 3D-Bioplotted polycaprolactone scaffolds with 100, 200, or 400 μm interstrand spacing were implanted subcutaneously in a rat model for 4, 8, or 12 weeks. Scaffolds were harvested, paraffin-embedded, sectioned, and stained to visualize cell nuclei and collagen. Quantitative image analysis was used to evaluate cell density, matrix fill, and collagen fiber alignment within the scaffolds. Results: By 4 weeks, cells had infiltrated the innermost scaffold regions. Similarly, collagenous matrix filled interstrand regions nearly completely by 4 weeks. By 12 weeks, aligned collagen was present in all scaffolds. Generally, alignment along the scaffold strands increased over time for all three interstrand spacing groups. Distribution of collagen fiber alignment angles narrowed as interstrand spacing decreased. Conclusions: 3D-Bioplotted scaffolds allow for complete cell infiltration and collagenous matrix production throughout the scaffold. The ability to use interstrand spacing as a means of controlling the formation of aligned collagen in vivo was demonstrated, which helps establish a design space for scaffold-based meniscus tissue engineering.}, number={3-4}, journal={CONNECTIVE TISSUE RESEARCH}, author={Warren, Paul B. and Huebner, Pedro and Spang, Jeffrey T. and Shirwaiker, Rohan A. and Fisher, Matthew B.}, year={2017}, pages={342–354} }
 @article{gaffney_warren_wrona_fisher_freytes_2017, title={Macrophages' role in tissue disease and regeneration}, volume={62}, journal={Macrophages: origin, functions and biointervention}, author={Gaffney, L. and Warren, P. and Wrona, E. A. and Fisher, M. B. and Freytes, D. O.}, year={2017}, pages={245–271} }
 @misc{cone_warren_fisher_2017, title={Rise of the Pigs: Utilization of the Porcine Model to Study Musculoskeletal Biomechanics and Tissue Engineering During Skeletal Growth}, volume={23}, ISSN={["1937-3392"]}, DOI={10.1089/ten.tec.2017.0227}, abstractNote={Large animal models play an essential role in the study of tissue engineering and regenerative medicine (TERM), as well as biomechanics. The porcine model has been increasingly used to study the musculoskeletal system, including specific joints, such as the knee and temporomandibular joints, and tissues, such as bone, cartilage, and ligaments. In particular, pigs have been utilized to evaluate the role of skeletal growth on the biomechanics and engineered replacements of these joints and tissues. In this review, we explore the publication history of the use of pig models in biomechanics and TERM discuss interspecies comparative studies, highlight studies on the effect of skeletal growth and other biological considerations in the porcine model, and present challenges and emerging opportunities for using this model to study functional TERM.}, number={11}, journal={TISSUE ENGINEERING PART C-METHODS}, author={Cone, Stephanie G. and Warren, Paul B. and Fisher, Matthew B.}, year={2017}, month={Nov}, pages={763–780} }