Elsevier

Biotechnology Advances

Volume 36, Issue 2, March–April 2018, Pages 521-533
Biotechnology Advances

Research review paper
Enabling personalized implant and controllable biosystem development through 3D printing

https://doi.org/10.1016/j.biotechadv.2018.02.004Get rights and content

Abstract

The impact of additive manufacturing in our lives has been increasing constantly. One of the frontiers in this change is the medical devices. 3D printing technologies not only enable the personalization of implantable devices with respect to patient-specific anatomy, pathology and biomechanical properties but they also provide new opportunities in related areas such as surgical education, minimally invasive diagnosis, medical research and disease models. In this review, we cover the recent clinical applications of 3D printing with a particular focus on implantable devices. The current technical bottlenecks in 3D printing in view of the needs in clinical applications are explained and recent advances to overcome these challenges are presented. 3D printing with cells (bioprinting); an exciting subfield of 3D printing, is covered in the context of tissue engineering and regenerative medicine and current developments in bioinks are discussed. Also emerging applications of bioprinting beyond health, such as biorobotics and soft robotics, are introduced. As the technical challenges related to printing rate, precision and cost are steadily being solved, it can be envisioned that 3D printers will become common on-site instruments in medical practice with the possibility of custom-made, on-demand implants and, eventually, tissue engineered organs with active parts developed with biorobotics techniques.

Introduction

Additive manufacturing has been slowly pervading to all aspects of life and is a driving force in a silent revolution in how we design, develop and manufacture products. Since early 80s, following the footsteps of the stereolithography breakthrough by Charles W. Hull, the advances in the production of 3D structures with a wide range of technologies have been achieved that enabled the additive manufacturing of different forms of materials. As a highly regulated domain, medicine has been, up to now, slow in uptake of 3D printing technologies due to the particular restrictions in the materials that can be used. However, as 3D printing field matured, technologies for printing clinically relevant materials with the required precision have evolved (Murphy and Atala, 2014). Currently, there are dedicated instruments that can print medical grade ceramics, metals and polymers for medical uses. There are many occasions where 3D printed implants, although mostly anecdotal or in limited series, have been used clinically (Di Prima et al., 2015). Also the availability of the technology has brought further innovations for the use of 3D printed structures (such as surgical simulation). ASTM and ISO standards currently recognizes 7 processes for additive manufacturing all of which has been adapted for medical use to a certain extent: These processes are: powder bed fusion, material extrusion, material jetting, binder jetting, sheet lamination, direct energy deposition and vat photopolymerization (ISO). This wide range of available technologies together with those under development provides a positive outlook for further establishment of 3D printing techniques for biomedical devices field.

Still, the portion of medical devices in overall 3D market, which is on its way to become a multibillion $ market, is <5%. One of the biggest roadblocks that leads to this is the disruptive nature of 3D printing technology; the methods used for 3D printing do not conform well with the processes developed for validation and quality checks of medical devices in use. Establishing the necessary validation process regarding customized 3D printed products (for example an instrument and non-invasive sampling based validation process rather than implant lot based validation) is an important step that needs to be taken together by the regulatory actors and industry. This is particularly crucial for bioprinting applications for which the final products will be by default Class III products or ATMPs (Advanced Therapeutic Medicinal Products) and thus have higher levels of regulatory constraints (where ISO standard 10993 for biocompatibility needs to be observed for example for both FDA approval and for obtaining CE mark). Moreover, the patient-specific shape and architecture also complicate validation of certain design parameters. For example, for a set implant design the mechanical failure analyses can be done via simulation or experimentally but for a unique implant this needs to be repeated for each implant as the specific shape based on anatomical constraints can weaken the overall structure. As preparing several samples of each implant for each patient for just testing is untenable, reliable simulation-based verification means needs to be implemented. However, this route has not been fully embraced by the regulatory bodies yet. Moreover, most of the 3D printed structures will have intricate interior designs which needs to be validated post-printing with non-invasive but robust methods, for example micro-CT validation of interior dimension fidelity (Hollister et al., 2016). In addition, possible compromises with the sterility can be also linked with the architectural differences between the implants and assuring the sterility might require additional steps, which is not necessary for conventional implants. Readers are referred to the cited reference which explains the difficulties and requirements of such validation processes for a 3D printed tracheobronchial splint for pediatric use (Morrison et al., 2015b). However, it should be noted that tracheobronchial splint has a well-defined reference design where several parameters are changed to optimize the final implant for a specific patient. This will not be the case for filling of defects or partial organ replacement, for example, and can further complicate the verification and validation processes.

Also, there are significant logistics related problems particularly for ATMPs produced by 3D bioprinting as the sourcing of the cells of the patient, the location of the printing and the fragile nature of the final products require a tight synchronization of diagnosis, clinical decision, implantable structure production, delivery and implantation. However, in the view of potential benefits for patients, healthcare system and overall society, the required amount of work to achieve this is reasonable. Moreover, bioprinting driven research in hydrogel 3D printing can have other overarching effects as recently demonstrated. Additive manufacturing of hydrogels can be used for design and implementation of implantable microelectromechanical systems where stimuli responsive hydrogels can function as barriers, valves, pumps etc. (Zorlutuna et al., 2013). A recent elegant example demonstrates the potential of using 3D printing for development of devices with soft controllable components. Using iron oxide nanoparticle doped photopolymerisable poly(ethyleneglycol) diacryate (PEGDA) hydrogels, Chin et al. demonstrated a wirelessly activated drug payload system that contains movable mechanical components for triggered release (Chin et al., 2017). This system was demonstrated to be effective in controlled delivery of doxorubicin, a widely used anti-cancer drug, and shown to be efficient at concentrations 1/10th of that is used in clinical practice.

In this review, we aim to provide a state of the art overview of the currently available bioprinting techniques and bioink formulations that are under development. This will be followed by use of 3D printing technologies for implantable devices with examples of clinical applications. Finally, the use of bioprinted structures beyond medical devices and regenerative medicine with recent examples will be introduced.

Section snippets

Bioprinting applications

Bioprinting is the 3D printing of artificial tissues and organs by precisely assembling the cells and natural or synthetic cell matrices, layer-by-layer to achieve highly accurate biomimetic constructs (Mandrycky et al., 2016; Wu et al., 2016b). Currently used conventional tissue engineering techniques remain insufficient for fabricating completely functional, vascularized tissues and organs (Ozbolat et al., 2016). In this regard, bioprinting techniques have enabled rapid development of the

Implantable 3D printed structures

The advantages of 3D printing can be divided into several categories. Those related to implantable devices are based on personalization which will be helpful for non-standard size patients and pathology related unique anatomical conditions. Moreover, 3D printing enables the development of multicomponent structures with site specific physical and mechanical properties which is not achievable with molding and potential temporal control over the implant properties when degradable materials are

Biorobotics

Recently, advances in tissue engineering and microfabrication techniques have led to the development of a new research field that explores the possibility of hybrid biological machines called biorobots (Feinberg, 2015; Kim et al., 2013). These synthetic biological systems or devices are composed of a soft biological component, such as living cells or muscle explants, incorporated into an artificial mechanical support. Usually, elastomeric materials such as polydimethylsiloxane (PDMS) or

Future directions

For medical applications two important challenges still remain for 3D printing. First one is the heterogeneous nature of the tissues that contain composites of multiple materials with distinct physicochemical properties. Thus, for implantable structures and bioprinting, it is desirable to have simultaneous printing of multiple materials which is not a trivial problem. Recently, Liu et al. reported multimaterial extrusion printing using a digitally controlled printhead (Liu et al., 2017). The

Acknowledgements

This study has received funding from EU FP7 IMMODGEL (Grant No. 602694), EU Horizon 2020 PANBioRA (760921) and FUI FASSIL (AAP-22-FASSIL) project. This study was supported by NSF Grants CBET-1530884 and ECCS-1611083.

References (134)

  • M. Hospodiuk et al.

    The bioink: a comprehensive review on bioprintable materials

    Biotechnol. Adv.

    (2017)
  • S. Kim et al.

    Soft robotics: a bioinspired evolution in robotics

    Trends Biotechnol.

    (2013)
  • S. Knowlton et al.

    Bioprinting for cancer research

    Trends Biotechnol.

    (2015)
  • Y. Komai et al.

    Patient-specific 3-dimensional printed kidney designed for "4D" surgical navigation: a novel aid to facilitate minimally invasive off-clamp partial nephrectomy in complex tumor cases

    Urology

    (2016)
  • D. Loessner et al.

    Bioengineered 3D platform to explore cell–ECM interactions and drug resistance of epithelial ovarian cancer cells

    Biomaterials

    (2010)
  • R. Mallik et al.

    Molecular motors: strategies to get along

    Curr. Biol.

    (2004)
  • C. Mandrycky et al.

    3D bioprinting for engineering complex tissues

    Biotechnol. Adv.

    (2016)
  • K. Markstedt et al.

    3D bioprinting human chondrocytes with Nanocellulose-alginate bioink for cartilage tissue engineering applications

    Biomacromolecules

    (2015)
  • F.P. Melchels et al.

    A poly (d, l-lactide) resin for the preparation of tissue engineering scaffolds by stereolithography

    Biomaterials

    (2009)
  • J. Norman et al.

    A new chapter in pharmaceutical manufacturing: 3D-printed drug products

    Adv. Drug Deliv. Rev.

    (2017)
  • C. Norotte et al.

    Scaffold-free vascular tissue engineering using bioprinting

    Biomaterials

    (2009)
  • I.T. Ozbolat

    Bioprinting scale-up tissue and organ constructs for transplantation

    Trends Biotechnol.

    (2015)
  • I.T. Ozbolat et al.

    Current advances and future perspectives in extrusion-based bioprinting

    Biomaterials

    (2016)
  • I.T. Ozbolat et al.

    Application areas of 3D bioprinting

    Drug Discov. Today

    (2016)
  • W. Peng et al.

    Bioprinting towards physiologically relevant tissue models for pharmaceutics

    Trends Biotechnol.

    (2016)
  • B. Raphael et al.

    3D cell bioprinting of self-assembling peptide-based hydrogels

    Mater. Lett.

    (2017)
  • A.A. Abdeen et al.

    Capturing extracellular matrix properties in vitro: microengineering materials to decipher cell and tissue level processes

    Exp. Biol. Med.

    (2016)
  • Y. Akiyama et al.

    Long-term and room temperature operable bioactuator powered by insect dorsal vessel tissue

    Lab Chip

    (2009)
  • Y. Akiyama et al.

    Atmospheric-operable bioactuator powered by insect muscle packaged with medium

    Lab Chip

    (2013)
  • A. Atala et al.

    Essentials of 3D Biofabrication and Translation

    (2015)
  • E. Bakirci et al.

    Cell sheet based bionk for 3D bioprinting applications

    Biofabrication

    (2017)
  • L.E. Bertassoni et al.

    Direct-write bioprinting of cell-laden methacrylated gelatin hydrogels

    Biofabrication

    (2014)
  • N.S. Bhise et al.

    A liver-on-a-chip platform with bioprinted hepatic spheroids

    Biofabrication

    (2016)
  • P.G. Campbell et al.

    Tissue engineering with the aid of inkjet printers

    Expert. Opin. Biol. Ther.

    (2007)
  • U.I. Can et al.

    Living diodes: muscle-cell-based “living diodes” (Adv. Biosys. 1-2/2017)

    Adv. Biosys.

    (2017)
  • M.P. Chae et al.

    3D-printed haptic “reverse” models for preoperative planning in soft tissue reconstruction: a case report

    Microsurgery

    (2015)
  • S. Chameettachal et al.

    Regulation of Chondrogenesis and hypertrophy in silk fibroin-gelatin-based 3D bioprinted constructs

    Acs Biomater. Sci. & Engineer.

    (2016)
  • V. Chan et al.

    Three-dimensional photopatterning of hydrogels using stereolithography for long-term cell encapsulation

    Lab Chip

    (2010)
  • V. Chan et al.

    Development of miniaturized walking biological machines

    Sci. Rep.

    (2012)
  • R. Chang et al.

    Biofabrication of a three-dimensional liver micro-organ as anin vitrodrug metabolism model

    Biofabrication

    (2010)
  • S.Y. Chin et al.

    Additive manufacturing of hydrogel-based materials for next-generation implantable medical devices

    Sci. Robotics

    (2017)
  • J.H.Y. Chung et al.

    Bio-ink properties and printability for extrusion printing living cells

    Biomater. Sci.

    (2013)
  • D.L. Cohen et al.

    Additive manufacturing forin siturepair of osteochondral defects

    Biofabrication

    (2010)
  • C. Colosi et al.

    Microfl uidic bioprinting of heterogeneous 3D tissue constructs using low-viscosity bioink

    Adv. Mater.

    (2016)
  • C. Cvetkovic et al.

    Three-dimensionally printed biological machines powered by skeletal muscle

    Proc. Natl. Acad. Sci.

    (2014)
  • A.B. Dababneh et al.

    Bioprinting technology: a current state-of-the-art review

    J. Manuf. Sci. Eng.

    (2014)
  • C. Debry et al.

    Implantation of an artificial larynx after Total laryngectomy

    N. Engl. J. Med.

    (2017)
  • M. Di Prima et al.

    Additively manufactured medical products–the FDA perspective

    3D Printing in Med.

    (2015)
  • M.C. Du et al.

    3D bioprinting of BMSC-laden methacrylamide gelatin scaffolds with CBD-BMP2-collagen microfibers

    Biofabrication

    (2015)
  • B. Duan et al.

    3D bioprinting of heterogeneous aortic valve conduits with alginate/gelatin hydrogels

    J. Biomed. Mater. Res. A

    (2013)
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