Review article3D printing for the design and fabrication of polymer-based gradient scaffolds☆
Graphical abstract
Introduction
Consideration of a tissue-engineered scaffold’s architecture on the macro-, micro- and nanoscale is crucial for proper nutrient and waste transport, cellular interactions, mechanical stability, and ultimately functional tissue formation [1]. Despite developments in material selection and scaffold design, it can still be difficult to achieve tissue biomimicry in these scaffolds, which significantly affects the resulting tissue regeneration [2]. As observed by Zhang et al., a scaffold carefully designed to mimic the architecture of the extracellular matrix (ECM) of native tissue can be expected to induce and direct cells to develop toward functional tissue [3]. In addition to the importance of material selection, inclusion of proper biochemical or biophysical stimuli could contribute to appropriate development. ECM can have specific spatial arrangement or be haphazardly organized depending on the type of tissue. Specific properties of the scaffold, if made to carefully mimic the native tissue, contribute to functional tissue formation. For example, scaffolds with uniform pore size and porosity similar to that of natural bone can lead to bone tissue formation [4]. Similarly, electrospun scaffolds with areas of poly(lactic-co-glycolic acid) (PLGA) fibers in an aligned or random orientation, designed to mimic collagen type I fibril orientation found in tendons, were created and seeded with fibroblasts [5]. Cells on aligned fibers elongated along the direction of the fibers and produced collagen type 1 in an organized fashion, as seen in native tendon fibroblasts. This approach, biomimicry of a component of the native environment, could be improved as research moves past biomaterial scaffolds with homogenously distributed composition or structural properties [6]. Native tissue often exists as a series of connected and graded transitional zones to build distinct functional regions. The lack of heterogeneity within previous scaffolds does not support the diverse populations of cells and surrounding environment of the native tissue. Thus, it is critical that the engineer incorporates graded properties within scaffolds to properly guide the development of new tissue. The advent of 3D printing and additive manufacturing has enabled the design of tissue scaffolds with precise designs incorporating graded properties that support the heterogeneous population of cells and matrix components that will eventually populate them.
3D printing, also referred to as additive manufacturing, rapid prototyping, or solid-freeform technology, emerged in a few fields in the mid 1980 s, and today has found industrial applications in the automotive, aerospace, construction, and even the cosmetic industry [7]. This technology has swept through the commercial world, transforming established practices and disrupting manufacturing techniques much like an industrial revolution, and has contributed to numerous biomedical applications within the research setting [8]. Specifically in the field of tissue engineering, 3D printing has been applied to virtually all tissues in the body and has even been utilized to fabricate whole organs [9].
Before the development of additive manufacturing techniques, tissue engineers used traditional scaffold fabrication techniques such as particulate leaching, electrospinning, phase separation, and gas foaming to achieve architectural variety in fabricated scaffolds [10]. While each of these methods have been extensively studied and optimized, they have inherent limitations. For example, these conventional methods are incapable of precisely controlling pore geometry, interconnectivity, and pore size, and especially of creating regions of variance within a single scaffold [11]. In addition, several of these techniques are contingent upon using organic solvents with inherent biocompatibility [12]. Additive manufacturing techniques allow the tissue engineers to circumvent these limitations through precise control over the design of the scaffold. This results in greater reproducibility, higher level details, and even patient-specific constructs [13].
This review focuses on additive manufacturing techniques that are being used to fabricate polymer-based, gradient scaffolds for tissue engineering. While these technologies are already being used to fabricate homogenous and patient-specific scaffolds, the true utility of these technologies is the level of architectural engineering they bring to the field of tissue engineering.
Section snippets
3D printing techniques
There is a vast assortment of 3D printing techniques developed and applied to the field of tissue engineering, with different approaches to reproducing a computer generated model. Within the constraints of the manufacturing method, the engineer can design the external and internal architecture that is to be built utilizing computer-aided design (CAD) software, informed through mathematical equations or values derived from clinical data [14]. CAD-based methods are the most widely used in the
Incorporation of gradients
As described, the human body is a complex multiphase system built from a dynamic interaction between 1) cells, 2) extracellular matrix, and 3) the resulting tissue architecture. In certain tissues, this system creates a microstructure that is highly graded in organization, chemical gradients, and mechanical properties [35]. These gradients contribute to critical processes such as embryogenesis, chemotaxis of polymorphonuclear leukocytes, and cell migration [36], [37], [38]. Additionally,
Evaluation of the achieved gradients
As described, gradient scaffolds are designed to meet a huge set of applications in tissue engineering. Looking collectively at the set described here, there are several analytical tools that are commonly used to investigate whether a gradient was achieved. Depending on the form of gradient, either biochemical or physical characteristic, different tools can provide information.
Challenges and perspectives of 3D printing for gradient scaffolds
The advent of additive manufacturing techniques within the field of tissue engineering has aided in the development of sophisticated biomaterials that better recapitulate the native tissue architecture. The complex heterogeneous microarchitecture of tissue plays a significant role in the differentiation and recruitment of diverse populations of cells. Thus, it is unsurprising that for successful tissue integration one would need to optimize the scaffold architecture to mimic this organized and
Acknowledgements
We acknowledge support by the National Institutes of Health (R01 AR068073, and the Armed Forces Institute of Regenerative Medicine (W81XWH-14-2-0004) for work in tissue engineering (A.G.M.). J.P.F. acknowledges support from the Maryland Stem Cell Research Fund (Grant # 4300811), and L.G.B. is supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health (Award Number F31 HL132541). We also acknowledge support from the Sheikh Zayed Institute for Pediatric
References (99)
- et al.
Gradient biomaterials for soft-to-hard interface tissue engineering
Acta Biomater.
(2011) - et al.
A review on stereolithography and its applications in biomedical engineering
Biomaterials
(2010) - et al.
Current trends in the design of scaffolds for computer-aided tissue engineering
Acta Biomater.
(2014) - et al.
Porous 3D modeled scaffolds of bioactive glass and photocrosslinkable poly (ε-caprolactone) by stereolithography
Compos. Sci. Technol.
(2013) - et al.
A poly (D, L-lactide) resin for the preparation of tissue engineering scaffolds by stereolithography
Biomaterials
(2009) - et al.
Design and development of three-dimensional scaffolds for tissue engineering
Chem. Eng. Res. Des.
(2007) - et al.
Fused deposition modeling of novel scaffold architectures for tissue engineering applications
Biomaterials
(2002) - et al.
Moving in the Right Direction: How Eukaryotic Cells Migrate Along Chemical Gradients, Seminars in Cell & Developmental Biology
(2011) Scaffolds in tissue engineering bone and cartilage
Biomaterials
(2000)- et al.
The influence of the scaffold design on the distribution of adhering cells after perfusion cell seeding
Biomaterials
(2011)
Effects of the architecture of tissue engineering scaffolds on cell seeding and culturing
Acta Biomater.
Design of porous scaffolds for cartilage tissue engineering using a three-dimensional fiber-deposition technique
Biomaterials
3D fiber-deposited scaffolds for tissue engineering: influence of pores geometry and architecture on dynamic mechanical properties
Biomaterials
Three-dimensional plotted scaffolds with controlled pore size gradients: effect of scaffold geometry on mechanical performance and cell seeding efficiency
Acta Biomater.
3D braid scaffolds for regeneration of articular cartilage
J. Mech. Behav. Biomed. Mater.
Matrix elasticity directs stem cell lineage specification
Cell
3D printing of porous hydroxyapatite scaffolds intended for use in bone tissue engineering applications
Mater. Sci. Eng. C
Dose-dependent cell growth in response to concentration modulated patterns of FGF-2 printed on fibrin
Biomaterials
Engineering spatial control of multiple differentiation fates within a stem cell population
Biomaterials
Inkjet-based biopatterning of SDF-1β augments BMP-2-induced repair of critical size calvarial bone defects in mice
Bone
Spatial regulation of controlled bioactive factor delivery for bone tissue engineering
Adv. Drug Deliv. Rev.
Inkjet printing of macromolecules on hydrogels to steer neural stem cell differentiation
Biomaterials
Fabrication of anatomically-shaped cartilage constructs using decellularized cartilage-derived matrix scaffolds
Biomaterials
Coextruded, aligned, and gradient-modified poly(ε-caprolactone) fibers as platforms for neural growth
Biomacromolecules
Additive manufacturing and mechanical characterization of graded porosity scaffolds designed based on triply periodic minimal surface architectures
J. Mech. Behav. Biomed. Mater.
Design of porous scaffolds for cartilage tissue engineering using a three-dimensional fiber-deposition technique
Biomaterials
A three-dimensional osteochondral composite scaffold for articular cartilage repair
Biomaterials
Digital image correlation and finite element modelling as a method to determine mechanical properties of human soft tissue in vivo
J. Biomech.
Biomaterials with persistent growth factor gradients in vivo accelerate vascularized tissue formation
Biomaterials
Engineering spatial control of multiple differentiation fates within a stem cell population
Biomaterials
Dose-dependent cell growth in response to concentration modulated patterns of FGF-2 printed on fibrin
Biomaterials
Three-dimensional plotted scaffolds with controlled pore size gradients: effect of scaffold geometry on mechanical performance and cell seeding efficiency
Acta Biomater.
Inkjet printing of macromolecules on hydrogels to steer neural stem cell differentiation
Biomaterials
Porous scaffold design for tissue engineering
Nat. Mater.
High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury
Arthritis Rheum.
Multiple facets for extracellular matrix mimicking in regenerative medicine
Nanomedicine
Inverse opal scaffolds for applications in regenerative medicine
Soft Matter
“Aligned-to-random” nanofiber scaffolds for mimicking the structure of the tendon-to-bone insertion site
Nanoscale
Evaluation of 3D printing and its potential impact on biotechnology and the chemical sciences
Anal. Chem.
3D printing disrupts manufacturing: how economies of one create new rules of competition
Res. Technol. Manage.
3D bioprinting of tissues and organs
Nat. Biotechnol.
Scaffold design and fabrication technologies for engineering tissues—state of the art and future perspectives
J. Biomater. Sci. Polym. Ed.
A review of rapid prototyping techniques for tissue engineering purposes
Ann. Med.
Making tissue engineering scaffolds work. Review: the application of solid freeform fabrication technology to the production of tissue engineering scaffolds
Eur. Cell Mater.
Review: polymeric-based 3D printing for tissue engineering
J. Med. Biol. Eng.
Development of a tissue engineering scaffold structure library for rapid prototyping. Part 2: parametric library and assembly program
Int. J. Adv. Manuf. Technol.
Development of a tissue engineering scaffold structure library for rapid prototyping. Part 1: investigation and classification
Int. J. Adv. Manuf. Technol.
Scaffolding in tissue engineering: general approaches and tissue-specific considerations
Eur. Spine J.
Poly (propylene fumarate) bone tissue engineering scaffold fabrication using stereolithography: effects of resin formulations and laser parameters
Biomacromolecules
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Part of the Gradients in Biomaterials Special Issue, edited by Professors Brendan Harley and Helen Lu.
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These authors contributed equally.