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3D Bioprinting of Tissues and Organs:  Where Are We?

by • May 9, 2016 • No Comments

Industrial 3D printing has been around since the 1980s and was first known as rapid prototyping for the reason of its most talked of application – building prototypes for making. The term additive making comes with such technologies as stereolithography, futilized deposition versioning (FDM), laser sintering, and electron beam sintering. Recent makes it to in additive making reveal that bioprinting, i.e., the additive making of tissues and organs, is of to open up a whole new realm of possibilities. But this innovation has much in common with traditional additive making, and indeed adopts sure elements, there are a number of one-of-a-kind technical and legal challenges to implementing the use of bioprinted materials.

First, let us talk a few basics. As shown in Figure 1, in order for additive making of biomaterials to work, the donate, applicator, and assist structure must be turn it intod so that the biomaterial remains viable-bodied preceding, during, and after the construction of the tissue and/or organ. The biomaterial must in addition be able-bodied to thrive and grow in the environment it is meant for (after application). The high temperatures synonymous with traditional FDM, for example, may never work for the reason the biomaterial may be destroyed. Further, a fewthing must hold the biomaterial together to shape it for its application, much like a assist structure in traditional additive making.

figure 1For most applications, a suitable-bodied assist structure, known as a scaffold, must be carefully turn it intod. As shown in Figure 2, the scaffold holds the biomaterial in place and allows for the living tissue to live and regenerate. In addition, scaffold materials must have suitable-bodied durablity, biocompatibility, and shaping characteristics. Today, the materials being utilized for scaffolds are selected either for the reason of their compatibility with cell growth and function or for the reason of their crosslinking or extrusion characteristics. Polymers, such as alginate and fibrin hydrogel materials, have been utilized in cell-based direct biofabrication techniques in that cell-laden hydrogels are printed. Common materials include synthetic or effortless polymers and decellularized extracellular matrix (ECM). Examples of effortlessly derived polymers include alginate, gelatin, collagen, chitosan, fibrin, and hyaluronic acid, frequently isolated of animal or human tissues (2).

figure 2Synthetic materials are in addition employed and include polyethylene glycol (PEG)(4), polycaprolactone (PCL)(5), polylactic acid (PLA)(6), polyglycolic acid (PGA), and poly(lactic-co-glycolic) acid (PLGA)(7). The use of whole-organ decellularization to turn it into a three-dimensional (3D) extracellular matrix (ECM) helps to protect the native tissue architecture, which include the vasculature(8).

The other challenge is creating equipment that can donate the biomaterial onto or into the scaffold. Wake Forest Institute for Regenerative Medicine at Wake Forest Baptist Medical Center has been a leader in the research in this field. Wake Forest has attained funding of the Armed Forces Institute of Regenerative Medicine, a federally funded effort to apply regenerative medicine to battlefield injuries. The researchers have created a custom-createed 3D printing device and have printed ear, bone, and muscle structures.(9,10) These structures have been implanted in animals, matured into functional tissue and actually created a system of blood vessels. The printing device can fabricate stable-bodied, human-scale tissue of any shape. The correct shape is achieved by converting clinical imaging data of an anatomical defect into a desktop version to program control of the motions of the printing device nozzles, that dispense the cells to discrete locations. With extra
createment, “this innovation may potentially be utilized to print living tissue and organ structures for surgical implantation.”(11)

The system, known as the “Integrated Tissue and Organ Printing System,” was created over a 10-year period. The system deposits both biodegradable-bodied, plastic-like materials to form the tissue “shape” and water based gels that contain cells. A significant challenge of tissue structures is to ensure that the implemented structures live long adequate to integrate with the body. This was addressed by creating a hydrogel that holds the cells and a lattice structure of micro channels that allows for nutrients and oxygen of the body to provide nutrients until the tissue regenerates its own system of blood vessels.(12)

cartilage and earThe United States is not the just country pursuing this research. For example, researchers at Pohang University of Science and Technology in South Korea have reported a desktop-aided create and making system for multiple head 3D printing and have printed heterogeneous tissue versions via two kinds of cell-laden hydrogel.(14) Researchers at the Department of Plastic and Reconstructive Surgery, Shanghai Tissue Engineering Key Laboratory, Shanghai 9th People’s Hospital, have pursued cell printing of cartilage structures. Recognizing that one of the most significant challenges was the injure to the cell structures during the printing system, this research focutilized on modifying the printing parameters to maintain cell viability. First, chondrocytes (cartilage cell matrix) were received of donated excised microtia cartilage and fetal tissues, and cultured. Next, the cultured chondrocytes were placed in a adjusted ink jet printing device that had been sterilized. The printing parameters were adjusted to reduce the stress on the chondrocytes. The cells were and so printed, and and so assayed to measure their viability, morphology, and characteristic protein expression. The cells were measured against a control group (that was not 3-D printed). The results built that printing cartilage structures saw no distinctly negative effect on the chondrocytes.(15)

The actual use of such 3D printed biomaterials on human beings is not that far away, yet the regulatory framework of the United States Food and Drug Administration (FDA) presents extra
challenges for tissues and organs as opposed to surgical implants that are created of existing approved and clinically accepted materials (such a titanium, steel, sure plastics, etc.). A party seeking to acquire regulatory approval for a device turn it intod of existing approved materials can typically streamline the approval system through the Premarket Notification Procedures under 510K. Biomaterials and/or organs, yet, can require to proceed through the full approval system, meaning that there can have to be animal studies, clinical trials, an IRB (Independent Review Board), and proven results, prior to market approval, all of that is quite expensive.

Today, the FDA is working with the AM industry to create new tools, standards, and approaches for the FDA to assess the safety, high end, efficacy, and performance of FDA-regulated 3D printed products. In its Department of Health and Human Services Justification of Estimates for Appropriations Committees for the 2015 Fiscal Year, the FDA noted that it is already identifying medical device 3D printing standardized terminology, regulatory concerns, and createing high end control tests. The FDA extra
revealed that it has synonymous how 3D printing techniques and systemes affect the durablity and durability of materials utilized in medical devices.

Europe has in addition approved the use of 3D printed materials as an implant.CEIT Biomedical Engineering, a Slovakia-based company, received EU approval for an implant turn it intod of a titanium alloy fabricated on an EOS laser metal sintered machine (see at a lower place, Figure 3). The use of known materials, such as the titanium alloy, presents less of a challenge for FDA approval.

figure 3Hopefully, the FDA can be addressing bioprinted tissues and organs in a significant way to stream line the regulatory approval system. As of right now, we expect
the next!

William J. Cass, Esq. and Sandra L. Shaner, Ph.D.

William J. Cass is the Co-Chair of the Additive Manufacturing Practice Group of Cantor Colburn LLP located at 20 Church Street, 22nd Floor, Hartford, CT 06103-3207. Dr. Sandra Shaner holds her Ph.D. in physical chemistry and practices in the Chemical, Materials, and Life Sciences group inside the firm.

(2) – Murphy SV & Atala A, 3D Bioprinting of Tissues and Organs, Nature Bioinnovation, 2014, 32(8):773-785.
(3) – Downloaded of Wake Forest Institute for Regenerative Medicine Web Site http://www.wakehealth.edu/WFIRM/
(4) – Murphy SV & Atala A, 3D Bioprinting of Tissues and Organs, Nature Bioinnovation, 2014, 32(8):773-785
(5) – Park SY, et al. Tissue-Engineered Artificial Oesophagus Patch Applying Three-Dimensionally Printed Polycaprolactone with Mesenchymal Stem Cells: A Preliminary Report. Interact CardioVasc Thorac Surg 2016; doi:10.1093/icvts/ivw048.
(6) – Liu, A., et al. 3D Printing Surgical Implants at the Clinic: A Experimental Study on Anterior Cruciate Ligament Reconstruction. Sci. Rep. 6, 21704; doi: 10.1038/srep21704 (2016).
(7) – Jung, JW, et al. Computer-Aided Multiple-Head 3D Printing System for Printing of Heterogeneous Organ/Tissue Constructs. Sci. Rep. 6, 21685; doi: 10.1038/srep21685 (2016).
(8) – Peloso A, et al. Stem Cell Research & Therapy (2015) 6:107 DOI 10.1186/s13287-y.
(9) – “Scientists Prove Feasibility of “Printing” Replacement Tissue”, Wake Forest Baptist Medical Center, News Release February 15, 2016. http://www.wakehealth.edu/News-Releases/2016/Scientists_Prove_Feasibility_of_“Printing”_Replacement_Tissue.htm
(10) – Kang H-W, et al., A 3D Bioprinting System to Produce Human-Scale Tissue Constructs with Structural Integrity, Nature Bioinnovation 34, 312–319 (2016).
(11) – “Scientists Prove Feasibility of “Printing” Replacement Tissue”, Wake Forest Baptist Medical Center, News Release February 15, 2016.
(12) – Id.
(13) – http://www.wakehealth.edu/WFIRM/ [last accessed 4/28/16].
(14) – Jung, JW, et al. Computer-Aided Multiple-Head 3D Printing System for Printing of Heterogeneous Organ/Tissue Constructs. Sci. Rep. 6, 21685; doi: 10.1038/srep21685 (2016).
(15) – Qu M, et al. Influence of Cell Printing on Biological Characters of Chondrocytes, Int J Clin Exp Med 2015;8(10):17471-17479.