Nicanor I. Moldovan

Bio: Nicanor I. Moldovan is an academic researcher from Indiana University – Purdue University Indianapolis. The author has contributed to research in topics: Biofabrication & Spheroid. The author has an hindex of 7, co-authored 11 publications receiving 332 citations.

Principles of the Kenzan Method for Robotic Cell Spheroid-Based Three-Dimensional Bioprinting*

Abstract: Bioprinting is a technology with the prospect to change the way many diseases are treated, by replacing the damaged tissues with live de novo created biosimilar constructs. However, after more than...

Principles of the Kenzan Method for Robotic Cell Spheroid-Based Three-Dimensional Bioprinting

Abstract: Bioprinting is a technology with the prospect to change the way many diseases are treated, by replacing the damaged tissues with live de novo created biosimilar constructs. However, after more than...

Progress in scaffold-free bioprinting for cardiovascular medicine.

Abstract: Biofabrication of tissue analogues is aspiring to become a disruptive technology capable to solve standing biomedical problems, from generation of improved tissue models for drug testing to alleviation of the shortage of organs for transplantation. Arguably, the most powerful tool of this revolution is bioprinting, understood as the assembling of cells with biomaterials in three-dimensional structures. It is less appreciated, however, that bioprinting is not a uniform methodology, but comprises a variety of approaches. These can be broadly classified in two categories, based on the use or not of supporting biomaterials (known as "scaffolds," usually printable hydrogels also called "bioinks"). Importantly, several limitations of scaffold-dependent bioprinting can be avoided by the "scaffold-free" methods. In this overview, we comparatively present these approaches and highlight the rapidly evolving scaffold-free bioprinting, as applied to cardiovascular tissue engineering.

A heuristic computational model of basic cellular processes and oxygenation during spheroid-dependent biofabrication.

Abstract: An emerging approach in biofabrication is the creation of 3D tissue constructs through scaffold-free, cell spheroid-only methods. The basic mechanism in this technology is spheroid fusion, which is driven by the minimization of energy, the same biophysical mechanism that governs spheroid formation. However, other factors such as oxygen and metabolite accessibility within spheroids impact on spheroid properties and their ability to form larger-scale structures. The goal of our work is to develop a simulation platform eventually capable of predicting the conditions that minimize metabolism-related cell loss within spheroids. To describe the behavior and dynamic properties of the cells in response to their neighbors and to transient nutrient concentration fields, we developed a hybrid discrete-continuous heuristic model, combining a cellular Potts-type approach with field equations applied to a randomly populated spheroid cross-section of prescribed cell-type constituency. This model allows for the description of: (i) cellular adhesiveness and motility; (ii) interactions with concentration fields, including diffusivity and oxygen consumption; and (iii) concentration-dependent, stochastic cell dynamics, driven by metabolite-dependent cell death. Our model readily captured the basic steps of spheroid-based biofabrication (as specifically dedicated to scaffold-free bioprinting), including intra-spheroid cell sorting (both in 2D and 3D implementations), spheroid defect closure, and inter-spheroid fusion. Moreover, we found that when hypoxia occurring at the core of the spheroid was set to trigger cell death, this was amplified upon spheroid fusion, but could be mitigated by external oxygen supplementation. In conclusion, optimization and further development of scaffold-free bioprinting techniques could benefit from our computational model which is able to simultaneously account for both cellular dynamics and metabolism in constructs obtained by scaffold-free biofabrication.

Mechanotransduction Effects on Endothelial Cell Proliferation via CD31 and VEGFR2: Implications for Immunomagnetic Separation.

Abstract: Immunomagnetic separation is used to isolate circulating endothelial cells (ECs) and endothelial progenitor cells (EPCs) for diagnostics and tissue engineering. However, potentially detrimental changes in cell properties have been observed post-separation. Here, we studied the effect of mechanical force, which is naturally applied during immunomagnetic separation, on proliferation of human umbilical vein endothelial cells (HUVEC), kinase insert domain-positive receptor (KDR) cells, and peripheral blood mononuclear cells (PBMCs). Cells were exposed to CD31 or Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) targeted MACSi beads at varying bead to cell ratios and compared to free antibody and unconjugated beads. A vertical magnetic gradient was applied to static 2D cultures, and a magnetic cell sorter was used to analyze cells in dynamic flow. No significant difference in EC proliferation was observed for controls or VEGFR2-targeting beads, whereas CD31-conjugated beads increased proliferation in a dose dependent manner in static 2-D cultures. This effect occurred in the absence of magnetic field, but was more pronounced with magnetic force. After flow sorting, similar increases in proliferation were seen for CD31 targeting beads. Thus, the effects of targeting antibody and magnetic force applied should be considered when designing immunomagnetic separation protocols for ECs.

Organ Printing: Tissue Spheroids as Building Blocks

Abstract: Organ printing can be defined as layer-by-layer additive robotic biofabrication of three-dimensional functional living macrotissues and organ constructs using tissue spheroids as building blocks. The microtissues and tissue spheroids are living materials with certain measurable, evolving and potentially controllable composition, material and biological properties. Closely placed tissue spheroids undergo tissue fusion - a process that represents a fundamental biological and biophysical principle of developmental biology-inspired directed tissue self-assembly. It is possible to engineer small segments of an intraorgan branched vascular tree by using solid and lumenized vascular tissue spheroids. Organ printing could dramatically enhance and transform the field of tissue engineering by enabling large-scale industrial robotic biofabrication of living human organ constructs with "built-in" perfusable intraorgan branched vascular tree. Thus, organ printing is a new emerging enabling technology paradigm which represents a developmental biology-inspired alternative to classic biodegradable solid scaffold-based approaches in tissue engineering.

A definition of bioinks and their distinction from biomaterial inks.

Abstract: Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384-402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks.

Biofabrication strategies for 3D in vitro models and regenerative medicine

Abstract: Organs are complex systems composed of different cells, proteins and signalling molecules that are arranged in a highly ordered structure to orchestrate a myriad of functions in our body. Biofabrication strategies can be applied to engineer 3D tissue models in vitro by mimicking the structure and function of native tissue through the precise deposition and assembly of materials and cells. This approach allows the spatiotemporal control over cell–cell and cell–extracellular matrix communication and thus the recreation of tissue-like structures. In this Review, we examine biofabrication strategies for the construction of functional tissue replacements and organ models, focusing on the development of biomaterials, such as supramolecular and photosensitive materials, that can be processed using biofabrication techniques. We highlight bioprinted and bioassembled tissue models and survey biofabrication techniques for their potential to recreate complex tissue properties, such as shape, vasculature and specific functionalities. Finally, we discuss challenges, such as scalability and the foreign body response, and opportunities in the field and provide an outlook to the future of biofabrication in regenerative medicine. Biofabrication can be applied to replicate tissues and organs for regenerative medicine and for the creation of 3D in vitro tissue models. In this Review, the recent advances in biomaterials and biofabrication technologies are discussed, and challenges and opportunities are highlighted.

3D Bioprinting: from Benches to Translational Applications.

Abstract: Over the last decades, the fabrication of 3D tissues has become commonplace in tissue engineering and regenerative medicine. However, conventional 3D biofabrication techniques such as scaffolding, microengineering, and fiber and cell sheet engineering are limited in their capacity to fabricate complex tissue constructs with the required precision and controllability that is needed to replicate biologically relevant tissues. To this end, 3D bioprinting offers great versatility to fabricate biomimetic, volumetric tissues that are structurally and functionally relevant. It enables precise control of the composition, spatial distribution, and architecture of resulting constructs facilitating the recapitulation of the delicate shapes and structures of targeted organs and tissues. This Review systematically covers the history of bioprinting and the most recent advances in instrumentation and methods. It then focuses on the requirements for bioinks and cells to achieve optimal fabrication of biomimetic constructs. Next, emerging evolutions and future directions of bioprinting are discussed, such as freeform, high-resolution, multimaterial, and 4D bioprinting. Finally, the translational potential of bioprinting and bioprinted tissues of various categories are presented and the Review is concluded by exemplifying commercially available bioprinting platforms.