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  1. 1. Running head: 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 1 3D Printing of Scaffolding for Aortic Valves Rina Bongalonta, Natalia Osorio, Daniel Patterson, Adrian Williams, Chris Wu University of South Carolina
  2. 2. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 2 Abstract The following paper discusses 3D printing using specified biomaterials in order to create effective aortic valve scaffolds for cardiac transplant. This paper covers the major reasons as to why patients must go through aortic valve transplants, such as the diseases affiliated with a malfunctioning aortic valve and the chronological progression of biomaterials and designs for scaffold models used for biovalves. The use of stem cells for cardiac valve scaffolds and the complications with current applications of in vivo aortic valves, such as Biovalve VII, are also explained. Future advances in aortic valve engineering are being made with alginate, or alginic acid/gelatin hydrogels, and human cardiac-derived cardiomyocyte progenitor cells (hCMPCs) to improve durability, permeability of bodily fluids, and keep foreign material deposits from collecting within the aortic valve. The main goal of biomedical engineer involvement is to create in vivo aortic valve scaffolds that are completely biocompatible with human transplantation and does not biodegrade. Public opinion and authority figures in scientific research are currently discussing the ethics and repercussions of 3D printing aortic valve construct and in vivo biomaterials for aortic valve transplant.
  3. 3. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 3 3-D Printing of Scaffolding for Aortic Valves In the event that an aortic valve must be replaced in the human body, three main categories of engineered valves that may be used: mechanical valves, biological prosthetics, and biovalves. Demonstrating the longest functional lifespan of over 25 years, mechanical valves are composed of materials such as titanium, polyester, and carbon compounds [1]. However, this option requires lifelong anticoagulation and can carry the risks of toxicity, thromboembolism, and bleeding in the patient [1]. Aortic valves can also be replaced by a biological prosthetic, originating from an organ donor or another animal source. The low availability of eligible human heart valves and ethical concerns are the reason that human donations are the least common choices for valvular transplants. Other cardiac tissue valves are harvested from pigs or cows and are treated so that the human body will not reject them [1]. While tissue valves have improved blood flow, lowered toxicity levels, and lessened the need for anticoagulation like the mechanical valves, tissue valves have shorter average life spans that last between 10 and 15 years due to tissue degradation [1]. Currently, unlike mechanical and tissue valves that lack the ability to grow or remodel, biovalves are the most promising option for patients in need of valve transplants [2]. In addition, biovalves are non-toxic, non-carcinogenic, and can be fabricated to many different shapes and sizes [2]. These valves are created by 3D printing a scaffold that is placed inside a living organism, promoting encapsulation with natural tissue growing on the scaffold. This process allows artificial valves with qualities such as tissue regeneration and self- repair to be manufactured most similarly to original aortic valves in the patients [1]. The most recently developed biovalve, Biovalve Type VII, demonstrates a large improvement towards engineering a fully-functioning in vitro aortic valve with the properties of a real aortic valve.
  4. 4. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 4 Biovalve Type VII Through 3D printing, molds can be made to allow in-body tissue engineering of aortic heart valves, with the most recent example being the Biovalve Type VII, as stated in “In-Body Tissue-Engineered Aortic Valve (Biovalve Type VII) Architecture Based on 3D Printer Molding.” By using a 3D printed the mold, the Biovalve VII can dictate tissue growth so that the prosthetic resembles the natural body tissue of a goat and can be removed without damage to the leaflet tissue. Goat models most resemble the conditions of humans through heart size and systemic circulation. The mold is implanted into the dorsal subcutaneous pouch of a goat, prompting connective tissue to encapsulate the mold, mimicking the natural leaflets in the goat’s aortic valve. After two months, the mold is completely enveloped by tissue, and the biovalves are harvested and tested. The valve formation has a 90 percent success rate, with 27/30 as functional. Using bypass surgery, three of the valves are implanted into goat models, where the valves are subjected to in vivo systemic circulation for one month. The other valves are tested for tensile strength, composition, and conditions of artificial systemic flow. In the goat models, the prosthetic valves maintained a low regurgitation rate (<3%) and kept a high opening ratio and are similar in both size and shape to the goat’s native sinus of Valsalva [3]. Progress Since the tissues are engineered in the body, the tissues are created without any artificial materials, unlike in vitro. Because the tissues are engineered in vivo, the valve is compatible with the body and acts in a similar manner to the natural body tissues, because the tissues come from the animal itself. Additionally, the highly ordered and complex methods of in vitro tissue engineering are not needed. Although the Biovalve VII shows improvement from the valve models used today, the Biovalve VII is prone to calcification and degeneration [3].
  5. 5. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 5 According to “Rapid manufacturing techniques for the Tissue Engineering of Human Heart Valves,” unlike the Biovalve VII, in order to make cardiac valves through in vitro methods, researchers used stem cells from the umbilical cord vein to engineer cardiac valves. Since the umbilical cord offers an abundance of stem cells, they are cryopreserved in liquid nitrogen to prevent from contamination until ready for use, after the cells are received. Once the cells were ready for use, they were then thawed and placed inside a pulsatile bioreactor, which combined the cell seeding process and conditioning process to prevent contamination. To achieve these processes, the pulsatile bioreactor has two cylindrical perfusion chambers that rotate in opposite directions: the perfusion chamber’s opposite directional rotation controls the supply of oxygen and the amount of turbulence to the cells. These extreme conditions created by the two cylindrical perfusion chambers are needed to seed the cells on to the scaffolds that create the cardiac scaffold [4]. Limitations While current applications of in vivo aortic valves (Biovalve VII) are intricately engineered to closely imitate the functions of native aortic valves, several biological issues arise, since these applications do not perfectly mirror the processes of native aortic valves. Several statistical analyses on the effectiveness of in vivo aortic valves show that failure is contingent on the individual’s age, with children and adolescents having the highest and fastest risk of failure and individuals over the age of 35 having the lowest and slowest [5]. This is due to the presence of developmental cardiac hypertrophy that is associated with the biological growth of adolescents. In these cases, four primary complications are the causes of failure: thrombosis/hemorrhage, endocarditis, structural dysfunction, and non-structural dysfunction [6]. Since the facilitation of native aortic valve structural properties is crucial to the success of in vivo
  6. 6. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 6 aortic valves, repetitive changes in structure and dimension, stress transfer to adjacent cardiac walls, and natural regression of damage are the primary causes of several structural dysfunctions [5]. In older individuals, in vivo aortic valves are usually subjected to calcification and stenosis, in which calcium deposits form within the cardiac tissue of the aortic valve causing vascular constriction. Although in vivo aortic valves have made much progress, future developments must be made to combat these biological problems. Future Bioprinting Research Currently, the development of in vivo biovalves using stem cells directly from the patient’s own tissue is in the conceptual stage. The limitations with constructing a viable scaffold model using the patient’s own cardiac cells include cell viability, medical complication after cell transfer, and opposing ethical standings. Presently, biomedical engineers use rapid prototyping (RP) techniques with computer based design and manufacturing to create complex and accurately detailed tissue constructs and models. Most of the efforts of bioprinting, such as gelatin hydrogels, stereolithography, which uses lithographic methods to 3D print models and prototypes one layer at a time, and two-photon laser based photo crosslinking for 3D tissues, have been geometrically inaccurate, cytotoxic, or not clinically adequate, respectively [7]. Therefore, biomedical engineers are current working on enhancing the standard of aortic valves by improving on the problems that are present with the current aortic valve scaffolds, such as Biovalve VII and standard polymer models. Members of the Department of Cardiology of the University Medical Center Utrecht in the Netherlands performed research on the amalgamation of current 3D printing and alginate hydrogels and progenitor cells, which helped design “biological materials that exhibit high resolution geometric and or mechanical complexity” [7]. The development for a supplementary
  7. 7. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 7 porous and permeable scaffold has been achieved using porous hydrogel models, especially that of the alginate type. Through natural in vivo aortic valve functional and structural fabrication, 3D printed models can have construct and the capability of cell regeneration, response stimuli, and viability, if the essential biomaterials are applied. In hydrogel models, alginate viscous gum, an anionic polysaccharide from the cell walls of brown algae, aids in material transfer between the linings of the scaffold and in concentration diffusion between the plasma and blood flowing through the aorta and the cells that are involved in tissue encapsulation with the implanted scaffold. The cardiac progenitor cells would also be biocompatible and adaptable to the in vivo communication and transport cells, thus preventing calcification and other aortic valve complications that are present in previous scaffold models. In the Department of Biomedical Engineering at Cornell University, a seven-day study compared the cell viability of a porous hydrogel scaffold containing progenitor cells versus the standard polymer cardiac valve model [8]. The aim of the study was to evaluate the combination of TP (tissue printing), human cardiac-derived cardiomyocyte progenitor cells (hCMPCs), and alginate hydrogels discs in three different shape models to obtain a construct with cardiogenic mechanical potential for in vitro or in vivo application. Porcine encapsulated aortic root sinus smooth muscle cells (SMC) and aortic valve leaflet interstitial cells (VIC) were examined and placed within a square, while vector and dumbbell shaped models of calcium chloride washed alginate/gelatin hydrogel scaffolds. General exposure and fluorescent staining were present throughout the experiment, and after the one-week period, cell viability was determined after printing. Ninety-two percent from the vector grid pattern hydrogel model and 89 percent of cells from the controlled standard polymer model were viable at 1 and 7 days of culturing [8]. Currently, the possibility of clinically examining scaffolds with progenitor cells and alginate
  8. 8. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 8 hydrogel material is still in processing to create a biocompatible, long lasting model for transplants with porcine cells and other sources [8]. Ethical Factors Although 3D printing has many benefits, such as producing not only aortic valves but also other parts of the human body, ethical issues surround the topic of 3D printing, like other technology in the world today. The article “3-D Printing Will Be a Counterfeiter’s Best Friend” discusses how much 3D printing can do for the human race in regards to improving our future. Ethical concerns arise when 3D printers allow for the the infringement of intellectual property and the market of fake IDs [9]. The AM systems, a company that allows for the affordable buying of products for pulmonary and respiratory care, has made it easier for people to get ahold of the products and produce the fakes. Even though 3D printing is fairly new, this issue seems to be a growing problem that will affect the future of 3D printing [9]. In the future, 3-D printing could raise the question of if it is ethical for one person to be able to receive an aortic valve over another person, because he or she is able to afford it, creating a greater barrier between the rich and the poor health-wise. The rich are allowed to live longer, because they can receive the benefits of 3D printing, while someone who makes less will not receive those same benefits. Three-dimensional printing can benefit everyone in the world, but if ethical issues like this continue, they can affect the public’s view on 3D printing [10]. In addition to economic ethical questions, the source of stem cells is controversial. The umbilical cord vein is considered more ethical for use because it does not require any extra surgery to receive it [4]. Although 3D printing allows for multiple medical benefits, such as the engineering of aortic valves, ethical concerns surround the practice of 3D printing.
  9. 9. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 9 References Mann, B.K., and West, J.L. (2001). Tissue Engineering in the Cardiovascular System: Progress Toward a Tissue Engineered Heart. The Anatomical Record, 263(4), 367-371. Jana, S., Lerman, A., Simari, R.D., and Spoon, D.B. (2014). Drug Delivery in Aortic Valve Tissue Engineering. Journal Of Controlled Release, 196, 307-323. Arakawa, M., Kanda, K. ,Kishimoto, Y., Matsui, Y., Nakayama, Y., Ohmuma, K., Oie, T., Sumikura, H., Tajikawa, T., Takewa, Y., Tatsumi, E., and Yamanami, M. (2015). In- Body Tissue-Engineered Aortic Valve (Biovalve Type VII) Architecture Based on 3D Printer Molding. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 103(1), 1-15. Hetzera, R., Jastramb, B., Luedersa, C., and Schwandtb, H. (2013). Rapid Manufacturing Techniques for the Tissue Engineering of Human Heart Valves. European Journal Cardio-Thoracic Surgery, 46(4), 593-601. Levy, R.J., Schoen, F.J. (1999). Tissue Heart Valves: Current Challenges and Future Research Perspectives. Journal of Biomedical Materials Research, 47(4), 439-465. Liebert, M.A. (2001). Development and Characterization of Tissue-Engineered Aortic Valves. Tissue Engineering, 7(1), 9-22. Alblas, J., Doevendans, P., Gaetani, Giacomello, A.,R., Messina, E., Metz, C., and Sluijter, J. (2012). Cardiac Tissue Engineering Using Tissue Printing Technology and Human Cardiac Progenitor Cells. Biomaterials, 33(6), 1782-1790. Butcher J.T., Duan B., Hockaday L.A., and Kang K.H. (2013). 3D Bioprinting of Heterogeneous Aortic Valve Conduits with Alginate/Gelatin Hydrogels. Journal Biomedical Materials Research Part A, 101A(5), 1255-1264.
  10. 10. 3D PRINTINGOF SCAFFOLDINGFOR AORTIC VALVES 10 Campbell, T., Cass, W. (2013). 3-D Printing Will Be a Counterfeiter's Best Friend. Scientific American. Dodds, S. (2015). 3D Printing Raises Ethical Issues in Medicine. ABC Science.