IU Indianapolis ScholarWorks :: Browsing by Author "Moldovan, Nicanor I."

Browsing by Author "Moldovan, Nicanor I."

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3D Printing of Human Ossicle Models for the Biofabrication of Personalized Middle Ear Prostheses
(MDPI, 2022-10-31) Dairaghi, Jacob; Rogozea, Dan; Cadle, Rachel; Bustamante, Joseph; Moldovan, Leni; Petrache, Horia I.; Moldovan, Nicanor I.; Physics, School of Science
The middle ear bones (‘ossicles’) may become severely damaged due to accidents or to diseases. In these situations, the most common current treatments include replacing them with cadaver-derived ossicles, using a metal (usually titanium) prosthesis, or introducing bridges made of biocompatible ceramics. Neither of these solutions is ideal, due to the difficulty in finding or producing shape-matching replacements. However, the advent of additive manufacturing applications to biomedical problems has created the possibility of 3D-printing anatomically correct, shape- and size-personalized ossicle prostheses. To demonstrate this concept, we generated and printed several models of ossicles, as solid, porous, or soft material structures. These models were first printed with a plottable calcium phosphate/hydroxyapatite paste by extrusion on a solid support or embedded in a Carbopol hydrogel bath, followed by temperature-induced hardening. We then also printed an ossicle model with this ceramic in a porous format, followed by loading and crosslinking an alginate hydrogel within the pores, which was validated by microCT imaging. Finally, ossicle models were printed using alginate as well as a cell-containing nanocellulose-based bioink, within the supporting hydrogel bath. In selected cases, the devised workflow and the printouts were tested for repeatability. In conclusion, we demonstrate that moving beyond simplistic geometric bridges to anatomically realistic constructs is possible by 3D printing with various biocompatible materials and hydrogels, thus opening the way towards the in vitro generation of personalized middle ear prostheses for implantation.
A dual osteoconductive-osteoprotective implantable device for vertical alveolar ridge augmentation
(Frontiers, 2022-01-04) Dairaghi, Jacob; Alston, Claudia Benito; Cadle, Rachel; Rogozea, Dan; Solorio, Luis; Barco, Clark T.; Moldovan, Nicanor I.; Surgery, School of Medicine
Repair of large oral bone defects such as vertical alveolar ridge augmentation could benefit from the rapidly developing additive manufacturing technology used to create personalized osteoconductive devices made from porous tricalcium phosphate/hydroxyapatite (TCP/HA)-based bioceramics. These devices can be also used as hydrogel carriers to improve their osteogenic potential. However, the TCP/HA constructs are prone to brittle fracture, therefore their use in clinical situations is difficult. As a solution, we propose the protection of this osteoconductive multi-material (herein called “core”) with a shape-matched “cover” made from biocompatible poly-ɛ-caprolactone (PCL), which is a ductile, and thus more resistant polymeric material. In this report, we present a workflow starting from patient-specific medical scan in Digital Imaging and Communications in Medicine (DICOM) format files, up to the design and 3D printing of a hydrogel-loaded porous TCP/HA core and of its corresponding PCL cover. This cover could also facilitate the anchoring of the device to the patient's defect site via fixing screws. The large, linearly aligned pores in the TCP/HA bioceramic core, their sizes, and their filling with an alginate hydrogel were analyzed by micro-CT. Moreover, we created a finite element analysis (FEA) model of this dual-function device, which permits the simulation of its mechanical behavior in various anticipated clinical situations, as well as optimization before surgery. In conclusion, we designed and 3D-printed a novel, structurally complex multi-material osteoconductive-osteoprotective device with anticipated mechanical properties suitable for large-defect oral bone regeneration.
Agent-Based Numerical Methods for 3D Bioprinting in Tissue Engineering
(Elsevier, 2018) Sego, T. J.; Moldovan, Nicanor I.; Tovar, Andres; Mechanical Engineering, School of Engineering and Technology
Additive manufacturing has contributed significantly to the development of new surgical and diagnostic aids, personalized medical devices, implants, and prostheses. Now, it aspires to the direct digital manufacturing of living tissue, organs, and body parts. This can be achieved using three-dimensional (3D) bioprinting techniques in which the printing medium consists of biomaterials and living cells. Several 3D bioprinting methods are currently available, including inkjet, extrusion, and stereolithography. An emerging approach is the creation three-dimensional cellular patterns by the use of cell spheroids. The optimal application and further development of 3D bioprinting techniques could largely benefit from computational models capable of predicting the complex behavior of the printed cellular structures on multiple scales. This book chapter summarizes the state of the art of computational models in this field, with an emphasis on agent-based approaches and cell spheroid-based 3D bioprinting.
Comparison of Biomaterial-Dependent and -Independent Bioprinting Methods for Cardiovascular Medicine
(Elsevier, 2017) Moldovan, Leni; Babbey, Clifford; Murphy, Michael; Moldovan, Nicanor I.; Department of Biomedical Engineering, School of Engineering and Technology
There is an increasing need of human organs for transplantation, of alternatives to animal experimentation, and of better in vitro tissue models for drug testing. All these needs create unique opportunities for the development of novel and powerful tissue engineering methods, among which the 3D bioprinting is one of the most promising. However, after decades of incubation, ingenuous efforts, early success and much anticipation, biomaterial-dependent 3D bioprinting, although shows steady progress, is slow to deliver the expected clinical results. For this reason, alternative ‘scaffold-free’ 3D bioprinting methods are developing in parallel at an accelerated pace. In this opinion paper we discuss comparatively the two approaches, with specific examples drawn from the cardiovascular field. Moving the emphasis away from competition, we show that the two platforms have similar goals but evolve in complementary technological niches. We conclude that the biomaterial-dependent bioprinting is better suited for tasks requiring faster, larger, anatomically-true, cell-homogenous and matrix-rich constructs, while the scaffold-free biofabrication is more adequate for cell-heterogeneous, matrix-poor, complex and smaller constructs, but requiring longer preparation time.
Design and Implementation of Anatomically Inspired Mesenteric and Intestinal Vascular Patterns for Personalized 3D Bioprinting
(MDPI, 2022-04-27) Cadle, Rachel; Rogozea, Dan; Moldovan, Leni; Moldovan, Nicanor I.; Surgery, School of Medicine
Recent progress in bioprinting has made possible the creation of complex 3D intestinal constructs, including vascularized villi. However, for their integration into functional units useful for experimentation or implantation, the next challenge is to endow them with a larger-scale, anatomically realistic vasculature. In general, the perfusion of bioprinted constructs has remained difficult, and the current solution is to provide them with mostly linear and simply branched channels. To address this limitation, here we demonstrated an image analysis-based workflow leading through computer-assisted design from anatomic images of rodent mesentery and colon to the actual printing of such patterns with paste and hydrogel bioinks. Moreover, we reverse-engineered the 2D intestinal image-derived designs into cylindrical objects, and 3D-printed them in a support hydrogel. These results open the path towards generation of more realistically vascularized tissue constructs for a variety of personalized medicine applications.
A Heuristic Computational Model of Basic Cellular Processes and Oxygenation during Spheroid-Dependent Biofabrication
(IOP, 2017) Sego, T. J.; Kasacheuski, Uladzimir; Hauersperger, Daniel; Tovar, Andres; Moldovan, Nicanor I.; Biomedical Engineering, School of Engineering and Technology
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.
iPSC-Derived Vascular Cell Spheroids as Building Blocks for Scaffold-Free Biofabrication
(Wiley, 2017) Moldovan, Leni; Barnard, April; Gil, Chang-Hyun; Lin, Y.; Grant, Maria B.; Yoder, Mervin C.; Prasain, Nutan; Moldovan, Nicanor I.; Biomedical Engineering, School of Engineering and Technology
Recently a protocol is established to obtain large quantities of human induced pluripotent stem cells (iPSC)-derived endothelial progenitors, called endothelial colony forming cells (ECFC), and of candidate smooth-muscle forming cells (SMFC). Here, the suitability for assembling in spheroids, and in larger 3D cell constructs is tested. iPSC-derived ECFC and SMFC are labeled with tdTomato and eGFP, respectively. Spheroids are formed in ultra-low adhesive wells, and their dynamic proprieties are studied by time-lapse microscopy, or by confocal microscopy. Spheroids are also tested for fusion ability either in the wells, or assembled on the Regenova 3D bioprinter which laces them in stainless steel micro-needles (the “Kenzan” method). It is found that both ECFC and SMFC formed spheroids in about 24 h. Fluorescence monitoring indicated a continuous compaction of ECFC spheroids, but stabilization in those prepared from SMFC. In mixed spheroids, the cell distribution changed continuously, with ECFC relocating to the core, and showing pre-vascular organization. All spheroids have the ability of in-well fusion, but only those containing SMFC are robust enough to sustain assembling in tubular structures. In these constructs a layered distribution of alpha smooth muscle actin-positive cells and extracellular matrix deposition is found. In conclusion, iPSC-derived vascular cell spheroids represent a promising new cellular material for scaffold-free biofabrication.
Labeling of endothelial cells with magnetic microbeads by angiophagy
(Springer, 2018-08) Thomas, Jessica; Jones, Desiree; Moldovan, Leni; Anghelina, Mirela; Gooch, Keith J.; Moldovan, Nicanor I.; Ophthalmology, School of Medicine
Objectives Attachment of magnetic particles to cells is needed for a variety of applications but is not always possible or efficient. Simpler and more convenient methods are thus desirable. In this study, we tested the hypothesis that endothelial cells (EC) can be loaded with micron-size magnetic beads by the phagocytosis-like mechanism ‘angiophagy’. To this end, human umbilical vein EC (HUVEC) were incubated with magnetic beads conjugated or not (control) with an anti-VEGF receptor 2 antibody, either in suspension, or in culture followed by re-suspension using trypsinization. Results In all conditions tested, HUVEC incubation with beads induced their uptake by angiophagy, which was confirmed by (i) increased cell granularity assessed by flow cytometry, and (ii) the presence of an F-actin rich layer around many of the intracellular beads, visualized by confocal microscopy. For confluent cultures, the average number of beads per cell was 4.4 and 4.2, with and without the presence of the anti-VEGFR2 antibody, respectively. However, while the actively dividing cells took up 2.9 unconjugated beads on average, this number increased to 5.2 if binding was mediated by the antibody. Magnetic pulldown increased the cell density of beads-loaded cells in porous electrospun poly-capro-lactone scaffolds by a factor of 4.5 after 5 min, as compared to gravitational settling (p < 0.0001). Conclusion We demonstrated that EC can be readily loaded by angiophagy with micron-sized beads while attached in monolayer culture, then dispersed in single-cell suspensions for pulldown in porous scaffolds and for other applications.
Of balls, inks and cages: Hybrid biofabrication of 3D tissue analogs
(2019) Moldovan, Nicanor I.; Moldovan, Leni; Raghunath, Michael; Biomedical Engineering, School of Engineering and Technology
The overarching principle of three-dimensional (3D) bioprinting is the placing of cells or cell clusters in the 3D space to generate a cohesive tissue microarchitecture that comes close to in vivo characteristics. To achieve this goal, several technical solutions are available, generating considerable combinatorial bandwidth: (i) Support structures are generated first, and cells are seeded subsequently; (ii) alternatively, cells are delivered in a printing medium, so-called “bioink,” that contains them during the printing process and ensures shape fidelity of the generated structure; and (iii) a “scaffold-free” version of bioprinting, where only cells are used and the extracellular matrix is produced by the cells themselves, also recently entered a phase of accelerated development and successful applications. However, the scaffold-free approaches may still benefit from secondary incorporation of scaffolding materials, thus expanding their versatility. Reversibly, the bioink-based bioprinting could also be improved by adopting some of the principles and practices of scaffold-free biofabrication. Collectively, we anticipate that combinations of these complementary methods in a “hybrid” approach, rather than their development in separate technological niches, will largely increase their efficiency and applicability in tissue engineering.
Principles of the Kenzan Method for Robotic Cell Spheroid-Based Three-Dimensional Bioprinting
(Liebert, 2017-06) Moldovan, Nicanor I.; Hibino, Narutoshi; Nakayama, Koichi; Biomedical Engineering, School of Engineering and Technology
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 a decade of incubation and many proofs of concept, the field is still in its infancy. The current stagnation is the consequence of its early success: the first bioprinters, and most of those that followed, were modified versions of the three-dimensional printers used in additive manufacturing, redesigned for layer-by-layer dispersion of biomaterials. In all variants (inkjet, microextrusion, or laser assisted), this approach is material (“scaffold”) dependent and energy intensive, making it hardly compatible with some of the intended biological applications. Instead, the future of bioprinting may benefit from the use of gentler scaffold-free bioassembling methods. A substantial body of evidence has accumulated, indicating this is possible by use of preformed cell spheroids, which have been assembled in cartilage, bone, and cardiac muscle-like constructs. However, a commercial instrument capable to directly and precisely “print” spheroids has not been available until the invention of the microneedles-based (“Kenzan”) spheroid assembling and the launching in Japan of a bioprinter based on this method. This robotic platform laces spheroids into predesigned contiguous structures with micron-level precision, using stainless steel microneedles (“kenzans”) as temporary support. These constructs are further cultivated until the spheroids fuse into cellular aggregates and synthesize their own extracellular matrix, thus attaining the needed structural organization and robustness. This novel technology opens wide opportunities for bioengineering of tissues and organs.

Browsing by Author "Moldovan, Nicanor I."

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