All Publications

  • Vascularized Bone-Mimetic Hydrogel Constructs by 3D Bioprinting to Promote Osteogenesis and Angiogenesis. International journal of molecular sciences Anada, T., Pan, C., Stahl, A. M., Mori, S., Fukuda, J., Suzuki, O., Yang, Y. 2019; 20 (5)


    Bone is a highly vascularized tissue with a unique and complex structure. Long bone consists of a peripheral cortical shell containing a network of channels for vascular penetration and an inner highly vascularized bone marrow space. Bioprinting is a powerful tool to enable rapid and precise spatial patterning of cells and biomaterials. Here we developed a two-step digital light processing technique to fabricate a bone-mimetic 3D hydrogel construct based on octacalcium phosphate (OCP), spheroids of human umbilical vein endothelial cells (HUVEC), and gelatin methacrylate (GelMA) hydrogels. The bone-mimetic 3D hydrogel construct was designed to consist of a peripheral OCP-containing GelMA ring to mimic the cortical shell, and a central GelMA ring containing HUVEC spheroids to mimic the bone marrow space. We further demonstrate that OCP, which is evenly embedded in the GelMA, stimulates the osteoblastic differentiation of mesenchymal stem cells. We refined the design of a spheroid culture device to facilitate the rapid formation of a large number of HUVEC spheroids, which were embedded into different concentrations of GelMA hydrogels. It is shown that the concentration of GelMA modulates the extent of formation of the capillary-like structures originating from the HUVEC spheroids. This cell-loaded hydrogel-based bone construct with a biomimetic dual ring structure can be potentially used for bone tissue engineering.

    View details for PubMedID 30836606

  • A Preclinical Induced Membrane Model to Evaluate Synthetic Implants for Healing Critical Bone Defects Without Autograft. Journal of orthopaedic research : official publication of the Orthopaedic Research Society DeBaun, M. R., Stahl, A. M., Daoud, A. I., Pan, C., Bishop, J. A., Gardner, M. J., Yang, Y. P. 2018


    Critical bone defects pose a formidable orthopaedic problem in patients with bone loss. We developed a preclinical model based on the induced membrane technique using a synthetic graft to replace autograft for healing critical bone defects. Additionally, we used a novel osteoconductive scaffold coupled with a synthetic membrane to evaluate the potential for single-stage bone regeneration. Three experimental conditions were investigated in critical femoral defects in rats. Group A underwent a two-stage procedure with insertion of a polymethylmethacrylate (PMMA) spacer followed by replacement with a 3D printed polycaprolactone(PCL)/beta-tricalcium phosphate (beta-TCP) osteoconductive scaffold after 4 weeks. Group B received a single-stage PCL/beta-TCP scaffold wrapped in a PCL-based microporous polymer film creating a synthetic membrane. Group C received a single-stage bare PCL/beta-TCP scaffold. All groups were examined by serial radiographs for callus formation. After 12 weeks, the femurs were explanted and analyzed with micro-CT and histology. Mean callus scores tended to be higher in Group A. Group A showed statistically significant greater bone formation on micro-CT compared with other groups, although bone volume fraction was similar between groups. Histology results suggested extensive bone ingrowth and new bone formation within the macroporous scaffolds in all groups and cell infiltration into the microporous synthetic membrane. This study supports the use of a critical size femoral defect in rats as a suitable model for investigating modifications to the induced membrane technique without autograft harvest. Future investigations should focus on bioactive synthetic membranes coupled with growth factors for single-stage bone healing. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30273977

  • Systematic characterization of 3D-printed PCL/beta-TCP scaffolds for biomedical devices and bone tissue engineering: Influence of composition and porosity JOURNAL OF MATERIALS RESEARCH Bruyas, A., Lou, F., Stahl, A. M., Gardner, M., Maloney, W., Goodman, S., Yang, Y. 2018; 33 (14): 1948–59
  • Tunable Elastomers with an Antithrombotic Component for Cardiovascular Applications. Advanced healthcare materials Stahl, A. M., Yang, Y. P. 2018: e1800222


    This study reports the development of a novel family of biodegradable polyurethanes for use as tissue engineered cardiovascular scaffolds or blood-contacting medical devices. Covalent incorporation of the antiplatelet agent dipyridamole into biodegradable polycaprolactone-based polyurethanes yields biocompatible materials with improved thromboresistance and tunable mechanical strength and elasticity. Altering the ratio of the dipyridamole to the diisocyanate linking unit and the polycaprolactone macromer enables control over both the drug content and the polymer cross-link density. Covalent cross-linking in the materials achieves significant elasticity and a tunable range of elastic moduli similar to that of native cardiovascular tissues. Interestingly, the cross-link density of the polyurethanes is inversely related to the elastic modulus, an effect attributed to decreasing crystallinity in the more cross-linked polymers. In vitro characterization shows that the antiplatelet agent is homogeneously distributed in the materials and is released slowly throughout the polymer degradation process. The drug-containing polyurethanes support endothelial cell and vascular smooth muscle cell proliferation, while demonstrating reduced levels of platelet adhesion and activation, supporting their candidacy as promising substrates for cardiovascular tissue engineering.

    View details for PubMedID 29855176

  • Synthesis and characterization of polycaprolactone urethane hollow fiber membranes as small diameter vascular grafts MATERIALS SCIENCE & ENGINEERING C-MATERIALS FOR BIOLOGICAL APPLICATIONS Mercado-Pagan, A. E., Stahl, A. M., Ramseier, M. L., Behn, A. W., Yang, Y. 2016; 64: 61-73


    The design of bioresorbable synthetic small diameter (<6mm) vascular grafts (SDVGs) capable of sustaining long-term patency and endothelialization is a daunting challenge in vascular tissue engineering. Here, we synthesized a family of biocompatible and biodegradable polycaprolactone (PCL) urethane macromers to fabricate hollow fiber membranes (HFMs) as SDVG candidates, and characterized their mechanical properties, degradability, hemocompatibility, and endothelial development. The HFMs had smooth surfaces and porous internal structures. Their tensile stiffness ranged from 0.09 to 0.11N/mm and their maximum tensile force from 0.86 to 1.03N, with minimum failure strains of approximately 130%. Permeability varied from 1 to 14×10(-6)cm/s, burst pressures from 1158 to 1468mmHg, and compliance from 0.52 to 1.48%/100mmHg. The suture retention forces ranged from 0.55 to 0.81N. HFMs had slow degradation profiles, with 15 to 30% degradation after 8weeks. Human endothelial cells proliferated well on the HFMs, creating stable cell layer coverage. Hemocompatibility studies demonstrated low hemolysis (<2%), platelet activation, and protein adsorption. There were no significant differences in the hemocompatibility of HFMs in the absence and presence of endothelial layers. These encouraging results suggest great promise of our newly developed materials and biodegradable elastomeric HFMs as SDVG candidates.

    View details for DOI 10.1016/j.msec.2016.03.068

    View details for Web of Science ID 000376547700008

    View details for PubMedID 27127029

  • Vascularization in Bone Tissue Engineering Constructs ANNALS OF BIOMEDICAL ENGINEERING Mercado-Pagan, A. E., Stahl, A. M., Shanjani, Y., Yang, Y. 2015; 43 (3): 718-729


    Vascularization of large bone grafts is one of the main challenges of bone tissue engineering (BTE), and has held back the clinical translation of engineered bone constructs for two decades so far. The ultimate goal of vascularized BTE constructs is to provide a bone environment rich in functional vascular networks to achieve efficient osseointegration and accelerate restoration of function after implantation. To attain both structural and vascular integration of the grafts, a large number of biomaterials, cells, and biological cues have been evaluated. This review will present biological considerations for bone function restoration, contemporary approaches for clinical salvage of large bone defects and their limitations, state-of-the-art research on the development of vascularized bone constructs, and perspectives on evaluating and implementing novel BTE grafts in clinical practice. Success will depend on achieving full graft integration at multiple hierarchical levels, both between the individual graft components as well as between the implanted constructs and their surrounding host tissues. The paradigm of vascularized tissue constructs could not only revolutionize the progress of BTE, but could also be readily applied to other fields in regenerative medicine for the development of new innovative vascularized tissue designs.

    View details for DOI 10.1007/s10439-015-1253-3

    View details for Web of Science ID 000351742500018

    View details for PubMedID 25616591