A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques

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Available online at www.sciencedirect.com

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Review Article

A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques

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Patrycja Szymczyk a, Magdalena Beata Labowska b, Jerzy Detyna b,*, Izabela Michalak c, Piotr Gruber a a

Department of Laser Technologies, Automation and Production Organization, Faculty of Mechanical Engineering, Lukasiewicza 5, 50-370 Wroclaw, Poland b Department of Mechanics, Materials Science and Bioengineering, Faculty of Mechanical Engineering, Wroclaw University of Science and Technology, Smoluchowskiego 25, 50-370 Wroclaw, Poland c Department of Advanced Material Technologies, Faculty of Chemistry, Wroclaw University of Science and Technology, Smoluchowskiego 25, 50-372 Wroclaw, Poland

article info

abstract

Article history:

This paper presents the current state-of-the art of additive manufacturing (AM) applications

Received 22 November 2019

in the biomedical field, especially in tissue engineering. Multiple advantages of additive

Received in revised form

manufacturing allow to precise three-dimensional objects fabrication with complex struc-

18 January 2020

ture using various materials. Depending on the purpose of the manufactured part, different

Accepted 24 January 2020

AM technologies are implemented, in which a specific material can be utilized. In the

Available online xxx

biomedical field, there are used several techniques such as: Binder Jetting, Material Extru-

Keywords:

focuses on the utilization of polymer materials (natural and synthetic) taking into account

sion, Material Jetting, Powder Bed Fusion, Sheet Lamination, Vat Polymerization. This article Additive manufacturing

hydrogels in scaffolds fabrication. Assessment of polymer scaffolds mechanical properties

3D printing

enables personalized patient care, as well as prevents damage after implantation in human

Biomaterials

body. By controlling process parameters it is possible to obtain optimised mechanical

Scaffolds

properties of manufactured parts.

Properties

© 2020 Nalecz Institute of Biocybernetics and Biomedical Engineering of the Polish

Applications

Academy of Sciences. Published by Elsevier B.V. All rights reserved.

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1.

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Additive manufacturing (AM) or rapid prototyping (RP) is a technology which allows to build three-dimensional struc-

Introduction

tures from digital data (3D model) by adding material layer-bylayer manner. This technological process is also called threedimensional (3D) printing and has been introduced by Charles W. Hull in 1986 [1–3]. To produce physical 3D objects in AM

* Corresponding author. E-mail address: [email protected] (J. Detyna). https://doi.org/10.1016/j.bbe.2020.01.015 0208-5216/© 2020 Nalecz Institute of Biocybernetics and Biomedical Engineering of the Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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technology it is necessary to use CAD 3D software or scanner (i.e., computerized tomography (CT), micro-CT, magnetic resonance imaging (MRI)) and then, create digital design file in CAD file [4,5]. In opposite to subtractive manufacturing technology to produce an object, AM technology depends on adding consecutively layer upon layer a portion of material [3,6–11]. In contrast to conventional manufacturing technologies advantages of additive manufacturing can be acknowledged. Technological progress in this area allowed to eliminate several limitations in manufacturing and enabled to obtain product more precisely with controlled dimension and more complex geometry without using traditional tools, with low manufacturing costs, in faster time and with minimum human intervention [6,12–17]. Mentioned strengths indicate that AM technologies shows high potential of providing a costeffective method of aiding or changing supply chain of complex and personalized medical products. Moreover there is a noticeable growth of medical industry driven by population ageing, increasing number of chronic diseases as well as dynamic development in emerging markets [18]. In 2018 size of AM global healthcare was estimated at USD 951.2 million and is expected to grow with a CAGR (Compound Annual Growth Rate) of 20.8% [19]. Under the term of 3D printing, different manufacturing methods can be distinguished, such as: Binder Jetting (e.g., Powder Bed Inkjet printing, S-printing, M-printing, ZipDose®), Directed Energy Deposition (e.g., Be Additive Manufacturing (BeAM), Direct Metal Tooling (DTM), Electron Beam Direct Manufacturing), Material Extrusion (e.g., Fused Deposition Modelling (FDM), gel or paste extrusion), Material Jetting (e.g., Inkjet printing, Polyjet), Powder Bed Fusion (e.g., Direct Metal Laser Sintering (DMLS), Selective Laser Sintering (SLS), Selective Metal Sintering (SLM)), Sheet Lamination (e.g., Laminated Object Manufacturing) and Vat Polymerization (e.g., Digital Light Projection (DLP), Stereolithography (SLA)) [4,6,20]. Generally, mentioned methods differ from each other by device construction and selection of suitable material for each method, layer bonding methods, efficiency of production, but also characteristic of the obtained object (e.g., geometric accuracy, surface finish, structure, mechanical properties) [20–24]. Depending on the type of method, it is possible to implement manufactured elements in various sectors of industry (i.e., aerospace parts, automobiles, art, construction, cosmetic industry, food industry, medicine, textile, toys, sport accessories) by using different materials (i.e., polymers (natural and synthetic), metal, ceramic, resins, or even living cells, but also merger of basic materials with additions like

nanomaterials (e.g., carbon nanofibers, carbon nanotubes, graphene)) [4,12,25,26]. Manufacturing complex structure while maintaining dimensional precision is one of the advantages in 3D printing applications, especially in bioengineering. Continuous technical development and research in material engineering provides opportunity to utilize of improved biomaterials in medical field [27]. The recent expansion of AM technologies has provided personalized patient care (e.g., possibility of a precise dose of the drug) [20,25]. Medical application of 3D printing is the most commonly used as an anatomical model (e.g., surgical planning tools used for training and education), in dentistry (e.g., braces, bridges, dentures, dental crowns bridges, prostheses, surgical guides), medical devices (e.g., implants, prostheses and orthoses, surgical instruments), pharmaceuticals (e.g., drug with controlled release, personalized medicines), organs, tissue and models (e.g., disease models and drug testing, tissue analogues for implantation, scaffolds) [20,25,28–30]. In Fig. 1, an example of custom-made implants is shown. Scaffolds, discussed in this paper and used in biomedical and tissue engineering, are highly porous 3D structures, which are used to replace or regenerate the native tissues in human body functionally and structurally. The aim of scaffolds is to allow cell activity such as migration, proliferation, attachment, and differentiation, even to enable oxygen and nutrients transportation [3,4]. Materials used for scaffolds production have to be biocompatible, easily sterilizable and non-toxic. The most commonly used materials are natural or synthetic polymers (e.g., hydrogels, proteins, thermoplastics, thermoplastic elastomers), metallic materials (e.g., titanium and magnesium alloys), bioactive ceramics and glasses and also composites of polymers and ceramics [32]. Numerous advantages of AM technology make it one of the most adequate methods for the building of complex scaffolds' architecture [4]. CAD software enables easy customization of applied scaffolds in human body [33]. Examples of additive manufactured 3D structures in form of scaffold are shown in Fig. 2. Final effect of the manufactured part is influenced by numerous factors, starting with method, material and finally adjustment of process parameters. One of the most important attribute in AM technology is accuracy, which is directly connected to process parameters. It determines quality and usability of final part and may have an impact on their mechanical properties [34]. Another significant feature of additive manufacture is mechanical characteristics, which

Fig. 1 – Example of: a) customized jaw implant for oncological treatment [31], b) patient-specific acetabular hip implants (Materialise, Belgium). Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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Fig. 2 – Examples of 3D scaffold structures manufactured using AM technology (own source).

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determines possible applications. Moreover, mechanical properties depend not only on the chosen material, but also geometry, layer thickness, air gap, fill pattern and temperature during model build process [35,36]. Most of the process parameters can be controlled, which gives the possibility of mechanical properties optimization, where also costs and time of production should be considered [36]. In this section it was gathered general description of AM technology with its most common techniques and potential application, notably in the biomedical sector, but also strengths and weaknesses of this technology and important factors to be taken into account during the production process. In the following chapters of this paper particular issues will be extended. The structure of present paper includes the description of Additive Manufacture techniques used in the biomedical field, especially with polymer scaffolds fabrication, the overview of polymer materials (synthetic and natural), with particular attention to hydrogels. It also contains evaluation of the mechanical properties of polymeric scaffolds with impact on the variability of process parameters during their production. The aim of this article is to present the currently used manufacturing methods of polymeric scaffolds with an overview of the materials utilized. Application of AM technologies in scaffolds fabrication enable the selection of wide range of polymeric materials, especially in the form of hydrogels. Potential utilization of scaffolds in biomedical field require the evaluation of their mechanical properties, especially with implantation in human body. Relevant strength of scaffolds is necessary to sustain structure in their initial shape during the patient's normal activities.

2. Additive manufacture technologies used in biomedical field The implementation of Additive Manufacturing in medicine allows personalization of the patient care. Promising area is novel drug delivery system, in which it is possible to precisely control the amount of dosed drug (e.g., tablets, pills, capsules) depending on individual patient's characteristics, disease state, age, gender, lifestyle, genetic profile, etc. In addition, it is possible to build complex geometries and structures, such as implants, prostheses, porous scaffolds, that cannot be produced with the same precision using traditional production methods. CAD software enables designing shape and geometry,

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which can be produced accurately and reproducible without resigning of customization [20,33,37]. Moreover, there is a possibility of combining multi-component pharmaceuticals and medication carriers, in which controlled release of the drug depends on applied materials (e.g., tablets). In the biomedical field there are used AM techniques such as: Material Extrusion (e.g., Fused Deposition Modeling (FDM), Gel or paste extrusion), Vat Polymerization (e.g., Stereolithography (SLA), Digital Light Projection (DLP)), Powder Bed Fusion (e.g., Selective Laser Sintering (SLS)), Binder Jetting (e.g., Powder Bed Inkjet printing), Material Jetting (e.g., Inkjet printing, Polyjet), Sheet Lamination (e.g., Laminated Object Manufacturing), as it is shown in Table 1. Each of the mentioned AM technology methods uses a different material that is bonded differently (e.g., by various energy sources, different physical state of the material). Desirable pharmaceuticals and medical facilities can be produced in this way. Early stages of AM technology allowed to make a product prototypes in short manufacturing time and cost-effectively. Nowadays, in comparison to the traditional manufacturing method, AM technology typically has advantage in lower cost of the material used (e.g., material saving) [38]. It is also an example of the elimination of the large-scale manufacture systems due to the compact size of the device used in AM technology [20]. As a result of the technological progress many methods have been developed in additive technologies. Unfortunately, only few are utilised in biomedical field, mainly due to more restrictive material requirements and the process conditions. Some manufacturing methods operate at high temperatures that could damage used material or additives (such as drug) [3,20]. In the Table 2, commonly used Additive Manufacturing methods applied in the biomedical field, such as FDM, binder jet printing, SLA, SLS with details about materials and their limitations have been gathered. Each technique of additive manufacturing has both benefits and disadvantages, not all types of materials can be used by each method, especially in the biomedical field, where used materials must be biocompatible and biofunctional [3].

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Fused deposition modelling

Fused Deposition Modelling (FDM) is widely propagated method of additive manufacturing technology, in which thermoplastic polymer in shape of wire (called filament) is melted and extruded through the nozzle with fine diameter. Processed material, in semi-liquid state, is added layer-bylayer. Each cross section is formed due to print-head movement (in X and Y axis). Recursive process results in building geometry based on three dimensional computer aided design (3D CAD) model [4,6,66]. In Fig. 3 scheme of this method is shown. FDM has many advantages, such as good efficiency, easy material replacement and its low costs of operation and implementation, furthermore, building process is automated and does not require the use of any tooling. FDM has also several limitations such as narrow selection of possible to process biomedical materials. Mechanical properties of thermoplastics processed using FDM in comparison to traditional manufacturing technologies are characterized by lower parameters, which results in a shorter lifetime of such products [6,34–36].

Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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Table 1 – Applications of AM techniques in biomedical field. Method Material Extrusion Fused Deposition Modeling (FDM)

Gel or paste extrusion

Vat Polymerization Stereolithography (SLA)

Digital Light Projection (DLP)

Principle of technology Selective extrusion of wire shaped thermopolymer

Selective extrusion of gel/paste

Polymerization of photocurable liquid resin initiated by laser

Solidification of photosensitive material by UV light modulated by several millions of micromirrors

Drug formulation * Tablets * Oral dispersible films * Capsules * Customized medicine for drug delivery * Dental fixtures, bridges and crowns * Customized patient specific implants and prostheses * Surgical models for perioperative surgical preparations * Scaffolds (tissue engineering, regenerative medicine) * Scaffolds for regeneration (bone, aortic valve, vasculature microfabrication, cartilage, neuronal, skeletal muscle, organ) * Cell cultures * Live tissue * Tablets (drug delivery models: immediate-release tablet, gastro-floating tablet, bilayer tablet, polypills)

References [21–29]

[37,40,41]

* Tablets

[7,39,42–44]

* * * * *

[45,46]

Personalised scaffolds Drug-loaded scaffolds Implantable devices Cell-containing hydrogels Spatially patterned tissue engineering scaffolds

* Complex organ structures (ear auricle, the cerebral sulcus and grooves, the heart with aorta and pulmonary artery/vein, the lung with thoracic cavity and the vascular network structures) Powder Bed Fusion Selective Laser Sintering (SLS)

Sintering or melting of a powder polymer with laser

* Orodispersible tablets * * * * *

Binder Jetting Powder Bed Inkjet printing

Bonding of a powder material with selectively jetted liquid binder

Material Jetting Inkjet printing

Polyjet

Deposing micro-droplets of liquid materials at high speed

Solidification of liquid photopolymers by UV light source

Lamination of sheet photopolymer material in a layer-by-layer by laser

[47–49,51,58– 60]

Surgical templates Drug delivery devices (implantable/subdermal) Oral dosage forms Resorbable devices

* Tablets * Controlled drug delivery device * Oral films and orally dispersible formulations * Microdots * Films * Anatomical models for surgical planning and pre-operative simulations (intrahepatic vessel models, liver models) * * * *

Sheet Lamination Laminated Object Manufacturing

Oral drug delivery systems Accelerated release formulations Dental parts Medical parts Scaffolds

* Reconstructive models

* * * *

[7,39,42,47– 58]

[42,61]

[37,62,63]

Solid dosage forms Dental delivery trays Surgical orthopaedic guides Hearing aids materials

* Anatomical models

[37,64,65]

* Models of soft tissue

Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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Table 2 – Methods of addition manufacture used in biomedical field. Method Fused Deposition Modeling (FDM)

Materials Continuous filaments of thermoplastics: * ABS,

* nylon, * PC, * PCL,

Stereolithography (SLA)

* * * * * * *

PLA PLLA, PLGA, PET-G, TPC, TPS PCL,

* PEGDA,

Selective Laser Sintering (SLS)

* PDL, * PDLLA, * PPF Polymers powders: * PEEK/HA,

* PCL, * PCL/HA,

Binder Jetting Bioprinting

* * * * *

PDLLA, PEEK, PLGA, PVA carbohydrates,

Limitations

Benefits

* Limited selection of materials used in biomedical field,

* Diverse range of geometries,

* Thermoplastic polymer used in this method cause shorter lifetime and poor mechanical characteristics, * Poor surface quality of printed objects, * Not preferred for biomedical implants, * Complications with incorporation of cells or bioactive molecules into filament

* Complex structures and shape,

* Limited number of materials (necessity of a photocrosslinkable material), * Limited number of potential materials (toxic substances during photopolimerisation)

* High dimensional accuracy,

References [3,6,33,35,44,115]

* Readily available filaments, * Time of manufacturing objects, * Affordability

[3,6,19,76]

* Intricate details,

* Smooth surface finish

* Using high temperature energy source, * Expensive technique,

* Large dimension of SLS device, * Resolution dependent upon powder microstructure and the spot size of the laser

* Poor adhesion between layers,

* polyvinyls,

* Poor surface quality,

* silica,

* Low mechanical properties

* Fast process,

[3,4,6,7,33,55]

* Manufacturing large and complex parts (irregular shapes and structures), * Material versatility, * Small series produced in one manufacturing process, * High part accuracy

* The cheapest and fastest method, * Wide range of used materials, * High precision of manufactured objects

[3,4,6,47]

* sucrose, * enable incorporation of biomolecules and drug PC - polycarbonate, PLLA - Poly (L-lactic acid), PPF - poly (propylene fumarate), TPS - thermoplastic starch.

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Due to poor surface finish, this method is not preferred for biomedical implants. The way to refine the surface roughness and to improve the mechanical properties is to lower layer thickness, but it increases production time and costs. Smooth surface finish of manufactured parts may be achieved by additional processes, like mechanical

and chemical finishing [12,35]. In order to extend the applications of FDM technology, it is necessary to improve properties of processed material, processability and reliability, but also the functionality of produced components [36]. In Fig. 4 examples of parts fabricated using FDM method are shown.

Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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Fig. 5 – Diagram of Selective Laser Sintering process (own source).

Fig. 3 – Scheme of Fused Deposition Modeling system (own source).

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Materials mainly used in Fused Deposition Modelling are acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), polycaprolactone (PCL), polyethylene terephthalate glycol (PET-G), tricalcium phosphate (TCP), nylon [33,66]. Unfortunately, there is a problem with incorporation of cells or bioactive molecules into filament at the stage of the production or this is usually inefficient process [6].

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Selective Laser Sintering/Melting (SLS/SLM) is one of the powder bed fusion technologies. Process of SLS is shown in Fig. 5. It uses heater, which preheats applied layer of powder material into build cavity (mainly metals and polymers, but also glass, ceramics) and laser radiation as a heating source for fusing (melting or sintering) desired cross sections. Layer-bylayer process of melting and subsequent solidification allows joining of individual layers, which results of three dimensional object, as shown in Fig. 6 [3,4,70]. It is worth mentioning that using material in powder form, allows to obtain/receive higher geometrical freedom of manufacturing.

Selective laser sintering/melting

In comparison to other processes, such as SLA or FDM, SLS bioprints usually exhibit better accurate detail and sharp reproduction. Accuracy is dependent upon the powder morphology (its flow behaviour, fluidization, particle shape and surface, particle size distribution) and upon the spot size of the laser, layer thickness, material shrinkage [3,4]. On the other hand, SLS bioprints exhibit excellent mechanical properties [6]. Significant disadvantage of this method is the use of high temperatures, especially instant high temperature due to laser radiation, which limits the number of materials that can be applied in bioengineering [33]. Materials used in SLS technology are mainly polymers but also ceramics. Tissue engineering scaffolds are produced most commonly using polymeric biomaterials and their composites (e.g., pure PCL, poly(D,Llactide) (PDLLA), poly(ether-etherketone) (PEEK), poly(lacticco-glycolic acid) (PLGA), poly(vinyl alcohol) (PVA), composite of polycaprolactone/hydroxyapatite (PCL/HA) or poly(etheretherketone)/hydroxyapatite (PEEK/HA)) [3,4].

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Stereolithography

Stereolithography (SLA) is the oldest process of AM technology, patented in 1986 by Charles Hull. SLA is one of vat photopolymerization methods, which uses ultraviolet laser to cure photopolymer resin. UV laser spot traces desired cross section starting a photopolymerization process, in which liquid material (resin) is solidified. System of SLA it shown in Fig. 7 [4,72]. Since only one material at time can be used, support structures are made of model material, and have to be manually removed after the process [4,73].

Fig. 4 – Examples of objects manufactured in FMD technique: a) cranial segment [67], b) tablets [68], c) dental model [69]. Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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2.4.

Fig. 6 – Scaffolds manufactured by SLM method [71].

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Binder Jetting

Binder Jetting is a method, which uses a liquid bonding agent and a powder-based material for manufacturing of object. Three dimensional objects are built using print-head, which selectively jets liquid agent according to the desired cross section which glues powder material [4]. Likewise in SLS technology, not bound powder material acts as a support structure, which allows to produce more complex geometries. That's why Binder Jetting can be used in tissue engineering in order to produce advanced and complex scaffold structures. Devices are inexpensive, moreover, unused powder can be used in the next process [3]. However, the lack of adhesion between layers and print resolution (range of 20–100 mm) in this technique is a challenges for the future [3,6]. This process can print a plurality of powder materials such as ceramics, metals, sand and polymers [4]. In the biomedical field, it is possible to process cells and hydrogel with the incorporation of biomolecules or drugs. Exemplary biomaterials used in this method are carbohydrates (e.g., sucrose), polyvinyls, silica [4,77]. Examples of manufactured objects in Binder Jetting are shown in Fig. 8.

3. The production of polymer scaffolds with additive manufacturing technologies

Fig. 7 – Process of Stereolithography method (own source).

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Significant disadvantage of using stereolithography in tissue engineering is the limited number of potential materials due to free radicals formation during photopolymerization process, which can damage cell membrane, protein, and nucleic acids [33]. Many researchers have carried out investigation with biomaterials to find a cytocompatible photoinitiator for SLA method [4]. For the production of porous 3D scaffolds, Elomaa et al. [74] used three-armed polycaprolactone (PCL) oligomers synthesized and end-functionalized with methacrylic anhydride. Hydrogel based polyethylene glycol (PEG) is used to create 3D structure of liver aggregates and microperfusion flow within the open channels of this structure [75]. For vascular applications, based on cell-laden hydrogel by poly-D-lysine (PDL), Elomaa et al. [74] used poly(ethylene glycol-co-depsipeptide) macromer. It is also possible to create cells-encapsulated hydrogel in complex 3D structure by using photopolymerizable poly(ethylene glycol) diacrylate (PEGDA) [76].

Scaffolds are 3D structures mainly utilised in the regeneration and tissue engineering. Porosity and pore size of scaffolds play an important role in biomedical applications. Maximum obtained porosity values range from 50 to 65%, whereas the minimum requirement for pore size is usually 100 mm due to the cell size, migration requirements and transport. Pore size higher than 300 mm is recommended in terms of enhanced new bone formation and the formation of capillaries [33,78,79]. Scaffolds structures can be implemented in the clinical uses such as bone grafts and substitute of bone material, growth factors, free fibrous transplantation and the incorporation of metalwork to aid bone stability, restoration, regeneration or replacement of injured or defective living tissue, cartilage and organs [4,26,80]. Open porosity is an important factor in designing and producing scaffolds. It ensures flow of the culture medium or blood and therefore continuous nutrients and metabolites supply, but also oxygen transport. Moreover, porous scaffolds enable tissue growth and ensure appropriate mechanical strength for transplantation and implantation in the human body, what contributes to the healing of complex tissue [3,4,33]. By production of biocompatible and biodegradable scaffolds it is possible to prepare implants out of cells procured from cell culture, which can be replaced after their dissolution by the natural tissue [33]. In this way, by integrating scaffolds into biomaterials design, tissue engineers could unlock cellular mechanisms, improve the reaction and regeneration of native tissues and contribute to the healing function [3]. In tissue engineering and regenerative medicine, 3D structures from biomaterials are often applied to basically all tissues in human body (e.g., blood vessels, bones, ears) and they are used to manufacture whole organs [2,12]. Initial scaffolds production methods were based on traditional

Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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Fig. 8 – Objects manufactured in Binder Jetting technique: a) heart model, b) backbone [59].

Fig. 9 – Example of polymer 3D scaffold manufactured in AM technology [82].

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manufacturing techniques, such as electrospinning, fiberbonding, melt molding, membrane lamination, particulate leaching, solvent casting and particulate leaching, thermally induced phase separation, and gas foaming [3,81]. In this way it was possible to achieve architectural miscellaneous in produced scaffolds due to the lack of the full control of the pores geometry. Nowadays, these complex and porous 3D structures are mainly produced using additive manufacturing (example in Fig. 9), which enables to eliminate traditional production methods' limitations. Precisely, by controlling pore geometry, connectability and pores size allow to increase repeatability, better detail reproduction and provide more effective personalisation of the manufactured scaffolds [3,12].

During polymer scaffolds manufacturing in tissue engineering it is important to take a suitable material into consideration, which will degrade and resorb in a controlled manner making place for new cells to form [83]. Bružauskaite et al. [84] described that the number of cells is dependent on the pore size. Physical properties of the bioresorbable scaffold should be retained until ingrowth tissue will be sufficiently strong and stiff to match the properties of the host tissue as closely as possible. Gradually disappearing scaffold matrix will start losing its mechanical properties and ought to be absorbed by the body without a foreign body reaction within a predetermined period of time [83,84]. Scaffold's material is required to be biocompatible, because in contact with human tissue it cannot induce inflammatory reactions and exhibit immunogenicity or cytotoxicity. Another feature to be implemented is its biodegradability, to allow development and growth of natural support structure after its degradation. In addition, scaffold's materials are supposed to be readily available and easy to manufacture. Moreover, to prevent infection, tissue scaffolds should be easily sterilizable [33,78,85]. Scaffolds used in the biomedical field, especially in tissue engineering, are manufactured from natural or synthetic polymers (e.g., hydrogels, proteins, thermoplastic elastomers and chemically cross-linked elastomers), bioactive ceramics (e.g., bioactive glasses, glass ceramics and calcium phosphates), ceramic and polymers composites and metallic materials (e.g., magnesium and titanium alloys) [4,32]. Mentioned biomaterials have some disadvantages: natural polymers may be characterized by poor mechanical properties, not all synthetic polymers are degradable and ceramics are too stiff. Unfortunately, there are only few biomaterials fulfilling all the requirements for scaffolds. To achieve functions and develop perfect biomaterial for bioengineering applications it is necessary to find the most appropriate combination of

Fig. 10 – Bioprinted 3D hydrogel constructions [87,88]. Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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materials of different origins [84,86]. The selection of suitable biomaterial in scaffolds production is very important since in certain processes bioactive molecules and living cells are incorporated into biomaterials (e.g., hydrogels, which example is shown in Fig. 10) [4]. Mechanical properties are one of the most important requirements for generation of scaffolds. Mechanical functionality and stability of this structure must be adequate to avoid structural damage during early postoperative function under physiologic loading conditions and patient's normal activities [78,85]. It is significant to keep the shape of scaffolds pores during the cell growth, which also requires a certain mechanical strength of the structure [4]. According to the mechanical strength, scaffolds can be classified as soft and hard tissues. Soft tissues (hydrogels) have a very high water content, they are flexible and it is possible to incorporate cells into hydrogels. Hard tissues (e.g., bones, teeth) in contrast to soft tissues are mineralized tissue and have a firm intercellular matrix. They are also known as calcified tissues [33].

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Hydrogels belong to the group of materials, which are used for biomedical applications, for example in tissue engineering (bone, cartilage, nerve, muscle, pancreas, and liver repair, regeneration or replacement), pharmaceutical applications (delivery of bioactive agents, e.g., drugs, proteins), wound healing (dressings), in vitro cell culture [89,90]. Hydrogels are gels formed from networks of hydrophilic, cross-linked polymer chains that absorb large amounts of water without dissolving [80,89,91]. There is a wide and diverse range of natural, biodegradable polymers and their derivatives that have been used to produce hydrogels, for example (1) anionic polymers such as hyaluronic acid, alginic acid, carrageenan, pectin, dextran sulphate, chondroitin sulphate, (2) cationic polymers such as chitosan and polylysine, (3) neutral polymers such as agarose, dextran and pullulan and amphipathic polymers such as collagen, fibrin and carboxymethyl chitin [87,90]. In addition to natural polymers, synthetic polymers can also be utilised to the synthesis of hydrogels (e.g., poly (acrylamide) (PAAM), poly(ethylene glycol) (PEG), poly(vinyl

Hydrogel materials for scaffold

9

Fig. 12 – Example of alginate scaffold structure [100].

alcohol) (PVA)). Due to the hydrophobic character of synthetic polymers and their chemical strength, they are characterized by higher mechanical strength in comparison to natural polymers, which makes them more durable and slower to degradation [92,93]. The flexible hydrophilic hydrogel structure can be produced using many techniques, especially these, which can be used to create a cross-linked polymer. Watersoluble linear polymers are cross-linked to form hydrogels in several ways: physical cross-linking (e.g., by crystallization, ionic interactions, hydrogen bonds), chemical cross-linking (e.g., by complementary groups chemical reaction, addition reactions, condensation reactions, free radical polymerization, using aldehydes, using enzymes), grafting polymerisation, and radiation cross-linking. The methods of hydrogel formation and their modifications can improve mechanical properties and viscoelasticity [92,94,95]. Examples of cross-linked alginate hydrogels are shown in Fig. 11. The main advantages of hydrogels are (1) high content of water — inclusion of growth media allows for cell encapsulation and growth and additionally the aqueous environment can protect cells and fragile drugs (2) crosslinking enables modification of mechanical properties, (3) good transport of nutrient to cells and products from cells, (4) release of drug/ growth factor can be controlled, (5) can be injected in vivo as a liquid that gels at body temperature, (6) ease of patterning via

Fig. 11 – Cross-linked alginate hydrogels a) high-purity, b) low-purity [96]. Please cite this article in press as: Szymczyk P, et al. A review of fabrication polymer scaffolds for biomedical applications using additive manufacturing techniques. Biocybern Biomed Eng (2020), https://doi.org/10.1016/j.bbe.2020.01.015

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3D printing to mimic tissue microarchitectures, (7) usually biocompatible [80,90]. Potential restrictions on the use of hydrogels include (1) difficulties in physical manipulation of constructs, (2) usually mechanically weak and mechanical properties can limit use in load bearing constructs, (3) optimising printing conditions for individual hydrogels can be time consuming, (4) difficulties in loading evenly with cells, (5) may be difficult to sterilize [80,90]. One of the biomaterials, that have numerous applications in biomedical science and engineering, is alginate (example of application in Fig. 12), which is a naturally occurring anionic copolymer obtained from brown seaweeds. It is composed of blocks of (1,4)-linked b-D-mannuronate (M) and a-L-guluronate (G) residues [89]. The physical properties of this polymer and hydrogels produced from alginate depend on the composition (e.g., M/G ratio), G-block length, and molecular weight [97]. With the increase of the length of G-block and molecular weight, mechanical properties of alginate gels are enhanced [89]. Crucial for these properties is also gelation temperature which influences gelation rate. At lower temperature, the reactivity of ionic cross-linkers (e.g., calcium ions) is reduced and the cross-linking is slower and the resulting network structure has greater order [98]. The main reasons for the popularity of the alginate as a biomaterial for biomedical applications are beside simple and fast gelation, low cost and non-immunogenicity [99]. The main usage of alginate hydrogels includes drug delivery, wound healing and tissue engineering applications [87,89]. This is possible due to favourable properties, such as ease of gelation after addition of for example calcium cations, biocompatibility and low toxicity [89,101]. The concentration of Ca(II) ions and sodium alginate in a hydrogel influence its swelling and mechanical properties [101]. Among mentioned applications, tissue engineering attracts the attention of scientists since it enables the manufacture of scaffolds for tissue/organs. One of the techniques used is 3D bioprinting with novel compatible biomaterials, including alginate hydrogels [4,87,102–104]. Customized-production, rapid-fabrication and high-precision are the main advantages of 3D bioprinting [4,102]. 3D bioprinting with alginate hydrogels is a novel platform which is used to construct complex 3D tissue architecture that mimic real ones [103]. Alginatebased hydrogels are known to have tunable mechanical properties (e.g., mechanical strength and stiffness) and they can be tailored to enhance printability and geometric accuracy [91]. There are two key properties of alginate-based bioink — viscosity and density that influence its printability [91,102]. Successful bioprinting of hydrogels depend on geometric accuracy and cell viability [105]. Some of the examples with a successful application of alginate-based hydrogels are available in the literature. For example, Wu et al. [103] developed a hybrid bioink composed of alginate and cellulose nanocrystals and used it to print a livermimetic honeycomb 3D structure that contained fibroblast and hepatoma cells. In the work of Yeo et al. [106], the bioink based on alginate and collagen was used in the innovative collagen-based cell-printing method to obtain human adipose stem cell-laden structures. In these structures, collagen-bioink was in the core region and the pure alginate in the sheath region to protect the cells in the collagen during the

printing and cross-linking process. Jia et al. [102] printed alginate solutions with human adipose-derived stem cells into lattice-structured, cell-laden hydrogels. Di Giuseppe et al. [91] used alginate-gelatin hydrogels for 3D bioprinting and tested the viability of encapsulated mesenchymal stem cells in the bioprinted construct.

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3.2.

Mechanical properties of AM manufactured scaffolds

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Structures built using AM technologies are evaluated in terms of their features — mechanical properties, e.g., tensile strength, flexural strength or impact resistance, but also dimensional and shape accuracy, and economic indicators such as production time and the amount of material used to produce the component [34]. Mechanical properties of parts fabricated using additive technologies are highly influenced by the used method and its process parameters, but also structure geometry and chosen material. In order to obtain desired mechanical properties with high quality, it is necessary to have structured knowledge of correlations between parameters in technological process and mechanical efficiency [35,36]. It is important to verify mechanical properties of the object manufactured using AM, due to various loads related to the selected application, like succumbing to deformations, dynamic stress and vibrations. Is also crucial implantation site examination. It can help design elements that could substitute damaged tissue. The most common reason of components failure is their plasticity under cyclic and dynamic loading conditions [40,107,108]. Depending on the method used, the mechanical properties of 3D printed samples may be affected by many factors, such as layer thickness, fill pattern and air gap between two adjacent deposited filaments in the same layer, structural orientation, scan speed and in some methods, the model's geometry, temperature and laser power [35,109]. Mechanical response can be influenced also by different defects occurred during manufacturing processes. This characteristics exhibits that mechanical response must be anisotropic and display tension/compression asymmetry [110]. Mohamed et al. [36] have shown, that mechanical response of polylactide (PLA) is better than the other investigated thermoplastic polymers and tensile strength of AM manufactured PLA is anisotropic. It was also presented, that polymers with low molecular weights achieved the highest tensile strength [36]. Mechanical properties differ depending on the build orientation and therefore samples manufactured along Z-axis have the lowest tensile strength [111]. Ceramic materials are characterized by a high mechanical strength. Moreover, researchers were able to produce component of Al2O3/ZrO2 with almost 100% density and flexural strength of more than 500 MPa [112]. In contrary, hydrogels do not provide high mechanical properties, therefore their application is limited. Nevertheless, the mechanical properties of hydrogels can be modified through crosslinking. Moreover, Gu et al. [4] showed that narrow pore size distribution, with adequate pore interconnectivity improved mechanical properties. Metals provide the highest mechanical properties, which can be favourable for slow bone growth applications. Unfortunately, these materials are not biodegradable and are suspected of releasing toxic metal ions [80].

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The pore diameter and its patterns have strong influence on the mechanical properties of scaffolds. Compression tests are carried out to check the strength of manufactured bone scaffolds [113]. Scaffold produced from sintered CaCO3 and SiO2 with porosity of up to 71% found maximum scaffold compressive strength of 28.1 MPa. Akremanite (Ca2MgSi2O7) with nano-titania particles was used to build a composite scaffold using SLS, with porosity of up to 58% which exhibited a maximum compressive strength of 23 MPa [80]. Furthermore, Zein et al. [81] showed that the fibres orientation in the layer also influenced mechanical properties of manufactured parts. They examined the influence of structure (direction of fibres in layers) and the size of porosity on the mechanical parameters such as stiffness, yield strength and yield strain [81]. Mechanical properties cannot be controlled by changing one factor, but it is necessary to control several parameters to achieve superior effects. Unfortunately, biodegradable materials tend to be mechanically unstable, thus mechanical strength and biodegradability are contradictory to each other [32]. Nevertheless, finding proper material is still an issue to be solved by researchers in the future. Connection of higher porosity and improvement of mechanical properties result also in higher in vitro cell growth, proliferation and mineralization of scaffold [80].

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maintain its mechanical properties until it is replaced by new growing tissue [83,84]. There are many challenges in the 3D printing to obtain optimised tissue architecture, biomaterials without defects and their desirable properties (e.g., biocompatibility, biodegradation, mechanical properties, printability). Research concerning the development of new materials exhibiting relevant characteristics and their compatible mechanical properties are the main aims of the modern tissue engineering [25,84].

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Declaration of interests

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None.

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CRediT authorship contribution statement

652

Patrycja Szymczyk: Conceptualization, Writing - original draft, Supervision. Magdalena Beata Labowska: Writing - original draft, Writing - review & editing. Jerzy Detyna: Conceptualization, Writing - original draft, Writing - review & editing, Project administration. Izabela Michalak: Writing - original draft, Writing - review & editing. Piotr Gruber: Writing - original draft, Writing - review & editing. Q4

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references

660

Conclusions and prospects for the future

Additive Manufacturing enables a wide range of industry applications, especially in the biomedical field [3]. In contrast to traditional methods, AM technologies are relevant in bioengineering, where it is important to produce personalized implants, to manufacture scaffolds with high accuracy and resolution, shape, geometry and complex matrix structure [3,20,33]. The possibility of using several biomaterials simultaneously decreases the production time and enables customization of drug dosage in a single medication [38]. AM technology also enables the precise manufacturing of the most important scaffold factor — open porosity, which allows the flow of nutrients and metabolites, as well as enables tissue growth and provides appropriate mechanical properties [3,4,33]. Biomaterials in AM technology, especially used in tissue engineering, ought to be biocompatible, easy biodegradable and sterilizable [33,78,85]. The most commonly used materials in tissue engineering are natural and synthetic polymers. Not all materials have suitable properties for human body applications [84]. Assessment of the mechanical properties of scaffolds implanted into the human body is very important. Damaged tissue, replaced by implanted tissue should maintain resistance to the load which is adequate to the location of the scaffold application [36,114]. Hydrogels usually exhibit poor mechanical properties, nonetheless they can be modified by crosslinking and provide a good environment for the cell growth and tissue regeneration [80,90]. By controlling process parameters in AM technology and proper selection of the material, it is possible to achieve desired mechanical properties [25,35,109]. The properties of the implanted scaffold should be similar to this of the host tissue and should be

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