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3D printed PLA-based scaffolds

3D printed PLA-based scaffolds Views a ND COmmeNtary Views a ND COmmeNtary Organogenesis 9:4, 239–244; October/November/December 2013; © 2013 Landes Bioscience A versatile tool in regenerative medicine 1,2 1,2 1,2,3 1,2, Tiziano Serra , Miguel A Mateos-Timoneda , Josep A Planell , and Melba Navarro * 1 2 Institute for Bioengineering of Catalonia (IBEC); Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Barcelona, Spain; Technical University of Catalonia (UPC); Barcelona, Spain apid prototyping (RP), also known Rapid prototyping (RP) has become part Ras additive manufacturing (AM), of the set of techniques currently used in has been well received and adopted in the development of new implants and 3D 1– 4 the biomedical field. The capacity of this scaffolds for tissue engineering. Owing family of techniques to fabricate custom- to their capacity to build custom-made ized 3D structures with complex geom- 3D structures, RP techniques have arisen etries and excellent reproducibility has special interest within the regenerative revolutionized implantology and regen- medicine community. In addition to revo- erative medicine. In particular, nozzle- lutionize implantology and regenerative based systems allow the fabrication of therapies by introducing new possibilities high-resolution polylactic acid (PLA) to reconstruct and regenerate tissues in a structures that are of interest in regen- patient-specific manner, RP also provides erative medicine. These 3D structures a tremendous tool to fabricate scaffolds find interesting applications in the regen - on demand to obtain in vitro platforms erative medicine field where promising for studying the effect of various param- applications including biodegradable eters such as scaffolds architecture, pore templates for tissue regeneration pur- size, geometry, topography, wettability, poses, 3D in vitro platforms for study- and mechanical properties among others, ing cell response to different scaffolds on cells behavior including inflammatory conditions and for drug screening are response. considered among others. Scaffolds func- Within the additive manufacturing tionality depends not only on the fabrica- techniques family, nozzle-deposition- Keywords: scaffolds, polylactic acid tion technique, but also on the material based ones have shown great versatility. (PLA), tissue engineering, rapid proto- used to build the 3D structure, the geom- The approach consisting in a controlled typing, biodegradable, drug screening, etry and inner architecture of the struc- dispensing system integrated with pump- 3D in vitro culture system, regenerative ture, and the final surface properties. All ing technology and a CAD/CAM system medicine, composite material, calcium being crucial parameters affecting scaf- allows the precise and reproducible fabri- phosphate glass folds success. This Commentary empha- cation of 3D structures with well-defined Submitted: 05/14/13 sizes the importance of these parameters predetermined geometries. In particu- Revised: 08/01/13 in scaffolds’ fabrication and also draws lar, the use of this technique to fabricate the attention toward the versatility of “high-resolution” polylactic acid (PLA) Accepted: 08/04/13 these PLA scaffolds as a potential tool in 3D structures has been recently reported http://dx.doi.org/10.4161/org.26048 regenerative medicine and other medical by us. In that work we describe the fab- *Correspondence to: Melba Navarro; fields. rication of PLA based scaffolds with dif- Email: [email protected] ferent geometries and provide valuable Introduction information on the importance of the dif- Commentary to: Serra T, Planell JA, Navarro M. ferent fabrication parameters on both bulk High-resolution PLA-based composite scaffolds Additive manufacturing techniques have and surface properties, and their impact via 3-D printing technology. Acta Biomater 2013; 9:5521-30; PMID:23142224; http://dx.doi. been welcome in the biomaterials field. on cell adhesion. In brief, both PLA and org/10.1016/j.actbio.2012.10.041 This family of techniques also known as PLA/glass scaffolds were 3D-printed www.landesbioscience.com Organogenesis 239 ©2013 Landes Bioscience. Do not distribute. Figure 1. sem images of biodegradable 3D structures with various materials, geometries and architectures, (A) PLa /CaP glass composite orthogonal structure; (B) PLa tubular hexagonal mesh; (C and F) Chitosan orthogonal-diagonal structure; (D) PLa orthogonal-displaced structure, (E) PLa hexago- nal mesh. using the nozzle-deposition-based system and architecture of the final structure, must be carefully tuned in order to obtain (Tissue Engineering 3-Dn-300, Sciperio/ and (3) surface properties of the scaffolds. such structures. However, if a completely nScrypt Inc., available in the Rapid different material such as a hydrogel or Prototyping service of the Biomedical Importance of Materials a PLA/glass composite material is used, Networking Center, CIBER-BBN, and in 3D Printing results are completely different. This is IBEC www.ibecbarcelona.eu/biomateri- the case of chitosan scaffolds, chitosan is a ls). Homogeneous polymer a nd polymer/ Choosing the right material is crucial a natural hydrogel that requires in situ glass solutions in chloroform (5% w/v) to achieve functional 3D structures. cross-linking to keep the scaffold struc- were prepared and printed at 3mm/s and Materials’ intrinsic properties may affect tural integrity. Moreover, chitosan swells a pressure between 40–80 psi, through both surface and bulk properties of the when in contact with aqueous media. a G27 (200 μm) nozzle. Structures final structure. Moreover, materials’ prop - Thus, structures with significantly larger with two different architectures were erties have a direct effect on the attainment struts diameter than the pre-defined ones fabricated: (1) orthogonal structures of certain predetermined geometries. All are obtained. (Fig. 1A) with distance between struts these aspects affect the mechanical prop- In the case of composite materials such axes (~500 μm) and struts diameter erties and the overall performance of the as PLA/glass particles, though the over- around ~70 μm, and (2) displaced dou- 3D scaffold. all structural results are the same as with ble-layer structures (Fig. 1D) with a dis- In the case of PLA, processing with the PLA, the increase of viscosity due to the tance between struts axes of ~250 μm already mentioned 3D printing tool allows addition of glass particles in the print- and two layers dispensed in each direc- obtaining highly precise structures with ing solution implies some changes in the tion. Structural, mechanical and surface better resolution than the ones obtained printing parameters and the morphology 6,7 properties of the developed scaffolds were with other currently used methods. of the final structures. Furthermore, from studied as well as in vitro cell adhesion. This improvement in resolution is due the morphological point of view, incor- Results shown in that work illustrate to a particular interplay between a set of poration of glass particles in the polymer and highlight the significance of factors temperature/plastiziser/printing param- matrix has a significant effect on surface such as: (1) the material used to fabri- eters and the post-processing shrinkage of topography. In addition, the presence of cate the 3D structure, (2) the geometry the struts due to solvent evaporation that glass particles in the scaffold affects the 240 Organogenesis Volume 9 issue 4 ©2013 Landes Bioscience. Do not distribute. mechanical behavior of the structure and on the compressive modulus of both scaf- wettability, surface electrical charges, and 8,9 its degradation rate. folds (E In fact, when 50% = 93.32 ± 2.18; E = free energy are also changed. As a result, orthogonal displaced of glass particles (<40 μm) are blended in 28.38 ± 3.99MPa; n = 3) as described by the affinity of some proteins and cellu- the polymer solution, the elastic modulus us. Thus, depending on the mechanical lar response for a particular substrate is of the structures increases substantially requirements of the final application, the altered. Nowadays, different techniques (PLA = 28.38 ± 3.99 MPa, PLA/glass = right material/design combination has to aimed to modify scaffolds’ surface have 5 15–18 44.19 ± 2.67 MPa; n = 3). Therefore, it be chosen in order to get the most ade- been developed, among them surface is clear that materials’ properties have to quated structures. functionalization with proteins or peptide be carefully considered since each material Additionally to struts’ orientation and sequences as well as the incorporation of requires different and specific processing conformation, struts’ thickness plays an an inorganic bioactive phase that triggers conditions, and each material leads to dif- important role. Thinner rods contrib- specific cell events have been successfully ferent structures. ute to increasing the specific area of the achieved. scaffolds considerably and therefore the Surface functionalization with bio- Design and Architecture contact area between material and cells active molecules. Coupling functional of 3D Scaffolds increases. However, diminishing struts groups, or specific biomolecules such as diameter implies that the number of f unctiona l peptides to the surface by mea ns Design and inner architecture of the 3D rods required to build a specific volume of chemical treatments is one the most structure strongly depends on its final increases and therefore longer fabrication currently studied methods for improving application; in this sense, a wide variety times are required. Nonetheless, higher biomaterials bioactivity. In this context, of geometries can be developed as the scaffolds resolution is a valuable asset as surface functionalization of the already ones depicted in Figure 1. An important pointed by Hollister et al. who stated mentioned PL A 3D printed scaffolds with parameter affecting cell response is the that one of the technical constraints of collagen has been investigated. Both, phy- scaffold geometry including pores size, currently used solid free form techniques sisorbed and covalently bonded collagen shape, and struts size and orientation in order to fulfil scaffolds translation to surface coatings have been achieved. In among others. Scaffolds architecture not clinic is their limitation in terms of feature the case of physical absorption, the scaf- only affects their mechanical performance size resolution to the hundreds of micron folds were directly immersed in a solution but also affects their permeability, nutri- scale. Albeit this is the case in most of containing collagen, whereas to achieve ents diffusion and cell response. Indeed, the work published in this area, the work covalent bonding the surface was previ- it has been reported that mesenchymal reported by us reveals that high resolution ously treated with NaOH + EDC /NHS in stem cells (MSCs) differentiation and pro- structures with features below the hun- order to activate the accessible functional liferation of pre-osteoblastic cells is highly dreds of microns are possible with nozzle- groups and subsequently immersed in affected by the geometry of individual based printing technology. the collagen solution (100 μg/ml in PBS, 11,12 pores within the scaffold. 24 h at room temperature). Both types Also, it has been published that the Enhancing Cell Response of samples were evaluated and character- separation between struts as well as by Controlling Surface Properties ized by CBQCA and Micro BCA assays the morphology of pores and the angle to evaluate the amount and distribution formed between struts affect macro- Overall, the success of a biomaterial of the biomolecule on the surface of the phages reponse. In fact, we have recently strongly depends on its interaction with scaffolds. The experiment was performed confirmed that the variation of scaffold the biological environment. There are in triplicate. As observed in Figure 2, geometry from an orthogonal configura - applications where a direct and tight con- fully and homogeneously collagen cov- tion (squared pores) to a diagonal con- tact between the tissue and the material ered scaffolds were obtained (Fig. 2A). figuration (triangular pores) (see Fig. 1 ) is required while there are other applica- In addition, a higher protein density was affects both macrophages morphology tions where a rather antifouling behavior quantified on the covalently function - and cytokine expression (data not shown). is needed. Hence, it is clear that bioma- alized scaffolds (Fig. 2C). Also, a cell Furthermore, orthogonal scaffolds pro- terials surfaces are crucial to enhance and viability assay was performed to measure moted the presence of rounded multinu- control the biological response of scaffolds cell adhesion on both non-functionalized cleated giant cells, whereas diagonal ones and implantable devices. Both surface and functionalized (covalently attached lead to elongated macrophages. chemistry and surface topography are the collagen) scaffolds. Mesenchymal stem Moreover, the distribution of struts most important features affecting bioma- cells (3 × 10 cells/scaffold) were seeded and their thickness may also affect sig- terials biological response. in the scaffolds, polystyrene microplate nificantly on the mechanical properties of Modification of surface chemistry is wells were used as control. Cell adhesion the final scaffolds. As a matter of fact, it the most direct way to inu fl ence protein was studied at 4 and 24 h using a LDH has been shown that by modifying scaf- adsorption and therefore cell behavior. By assay kit. Results shown in Figure 2D are folds geometry from an orthogonal design tailoring functional groups available at the expressed as the average absorbance levels to a displaced or shifted one (Fig. 1A material surface it is possible to modify its of three samples (Fig. 2D). An ANOVA and D), there is a substantial variation surface properties, and consequently its analysis was performed to establish www.landesbioscience.com Organogenesis 241 ©2013 Landes Bioscience. Do not distribute. Figure 2. s urface functionalization of PLa 3D scaffolds: ( A) Fully and homogeneously collagen covered scaffold; ( B) rms Cs cultured on the functional- ized scaffolds after 72 h; ( C) Quantification of the amount of collagen on the scaffolds surface. Covalently functionalized scaffolds showed a signifi- cantly higher protein density than physisorbed ones; (D) LDH assay of adhered rms Cs after 4 and 24h of culture on both covalently- and non-function- alized PLa scaffolds. Functionalized scaffolds showed a higher number of viable cells after 24h. t he values marked with asterisk (*) showed statistical significant differences ( P ≤ 0.05). possible statistical significant differences and spreading of cells on G5 glass parti- Addition of G5 particles into the 10,21 (P ≤ 0.05) in the absorbance values. Cell cles than in the polymer matrix. This polymer matrix introduced an interest- studies showed a positive cell response in soluble glass degrades along time while ing topography to the scaffold surface as the functionalized scaffolds. In fact, after releasing different ions to the surround- observed in Figure 3A and B. In addition, 72 h of culture, mesenchymal stem cells ing media. It has been demonstrated that the surface of the polymer struts showed were very well spread and completely cov- the presence of G5 glass particles not only micro and nanopores left by the evapora- ering the scaffold surface (Fig. 2B). increases cell attachment and spreading tion of the solvent (see Fig. 3C). Thus, the Improving surface bioactivity by add- but also triggers angiogenesis and bone final structures presented a combination 2+ ing inorganic particles. As previously formation owing the Ca release and stiff- of porosities and other topography features 22,23 mentioned, other method for modifying ness of the glass. Indeed, several stud- ranging from the macroscale due to the surface chemistry is by adding bioactive ies have demonstrated the relevant role pores initially designed to the micro and 24,25 inorganic particles to the PLA matrix. In of ions on tissue regeneration. Given nanoscale due to solvent evaporation and this line, addition of a soluble, bioactive that the glass particles incorporated into the presence of glass particles. According 19,20 CaP glass, known as G5, in particles the polymer scaffold are partially exposed to the interferometry results, the addition shape to reinforce and improve bioactivity in the surface, as demonstrated by an of glass particles significantly increased of PLA scaffolds has been explored. It is alizarin red assay (where only the calci- the average roughness (Sa) of the surface known that G5 glass is highly hydrophilic fied inorganic phase is stained in red color, in comparison to PLA (PLA = 117.72 ± (contact angle = 29.8°). Thus, addition Fig. 3D), their presence contribute both 60.50 nm, PLA/glass = 1003.89 ± 228.45 of G5 particles contributes to decrease to modify surface chemistry and surface nm; n = 9). It is known that both surface PLA contact angle. Previous studies have topography. micro and nanoporosity play important demonstrated a preferential attachment roles in protein adhesion and therefore 242 Organogenesis Volume 9 issue 4 ©2013 Landes Bioscience. Do not distribute. Figure 3. sem images of (A and B) PLa /CaP glass composite scaffolds showing glass distribution and glass/polymer interface, white arrows indicate glass particles; (C) s truts of a PLa scaffold showing the micro and nanoporosity left after solvent evaporation; ( D) PLa /CaP glass scaffold after a lizarin red staining. r ed colored areas denote the CaP inorganic phase indicating the glass particles exposed on the scaffold surface. on cell response. Surface nanoporos- their interaction is stronger. Thus, con- cells’ morphology when comparing both ity not only increases the contact surface trolled nanoporosity might play an impor- types of scaffolds. After 4 h, immunofluo - area between the material and biological tant role in biological interactions. rescence images showed well spread cells entities but also generates nanoscale topo- We reported on the results of rMSCs with extended cytoskeleton on the scaf- graphical cues affecting cell behavior. In response to PLA and PLA/CaP glass scaf- folds with CaP glass particles and rela- fact, enhancement of cell interaction due folds with similar architecture at short peri- tively rounded cells on the PLA scaffolds. 27,28 to nanotopography has been reported. ods of time. Cell viability (WST assay, n = Thus, the obtained results suggested clear Cells do not interact directly with bio- 3) and morphology (confocal microscopy early cell morphological differences due to materials, but with an absorbed protein observation upon nuclei and cytoskeleton topographical and chemical changes. layer that provides anchoring sequences to staining) were evaluated after 4 and 24 h cells. Protein adsorption is highly depen- of adhesion in contact with the materials. Conclusions dent on surface properties; in particular, Results revealed that although both mate- it is believed that since the dimensions of rials displayed similar cell viability results, Data reported by us is a glimpse that surface nanofeatures are closer to proteins, noteworthy differences were observed in opens new possibilities to produce novel www.landesbioscience.com Organogenesis 243 ©2013 Landes Bioscience. Do not distribute. 2. Hutmacher DW, Schantz JT, Lam CXF, Tan KC, 17. Miyagi Y, Chiu LL, Cimini M, Weisel RD, Radisic PLA scaffolds with finely tuned architec - Lim TC. State of the art and future directions of M, Li RK. Biodegradable collagen patch with cova- scaffold-based bone engineering from a biomaterials lently immobilized VEGF for myocardial repair. tures at a higher resolution than currently perspective. J Tissue Eng Regen Med 2007; 1:245- Biomaterials 2011; 32:1280-90; PMID:21035179; used methods. As described in the previ- 60; PMID:18038415; http://dx.doi.org/10.1002/ http://dx.doi.org/10.1016/j.biomaterials.2010.10.007 term.24 ous sections, the success of 3D scaffolds 18. Chung HJ, Park TG. Surface engineered and drug 3. Moroni L, Elisseeff J. Biomaterials engineered for releasing pre-fabricated scaffolds for tissue engi- depends on the combination of the appro- integration. Mater Today 2008; 11:44-51; http:// neering. Adv Drug Deliv Rev 2007; 59:249-62; priate materials with the right design and dx.doi.org/10.1016/S1369-7021(08)70089-0 PMID:17482310; http://dx.doi.org/10.1016/j. addr.2007.03.015 4. Yeong W Y, Chua CK, Leong K F, Chandrasekaran M. the right fabrication technique and fabri- Rapid prototyping in tissue engineering: challenges 19. Navarro M, Ginebra MP, Clement J, Martinez S, cation conditions that lead to the attain- and potential. 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Control of microenviron- erated; but also, in drug screening and in 6462(02) 00071-4 mental cues with a smart biomaterial composite certain malignancies therapeutics such as promotes endothelial progenitor cell angiogenesis. 8. Navarro M, Ginebra MP, Planell JA, Barrias CC, in cancer. Three-dimensional scaffolds Barbosa M A. In vitro degradation behavior of a novel Eur Cell Mater 2012; 24:90-106, discussion 106; PMID:22828988 bioresorbable composite material based on PLA and provide an environment able to recapitu- a soluble CaP glass. Acta Biomater 2005; 1:411-9; 23. Vila OF, Bagó JR, Navarro M, Alieva M, Aguilar late in vivo conditions in a more resem- PMID:16701822; http://dx.doi.org/10.1016/j.act- E, Engel E, Planell JA, Rubio N, Blanco J. Calcium bio.2005.03.004 bling way than traditional 2D in vitro cell phosphate glass improves angiogenesis capacity of poly(lactic acid) scaffolds and stimulates differentia- 9. Navarro M, Aparicio C, Charles-Harris M, culture systems. 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A PLA/calcium phosphate In the same direction, it could be degradable composite material for bone tissue engi- 2012; 9:401-19; PMID:22158843; http://dx.doi. org/10.1098/rsif.2011.0611 neering: an in vitro study. J Mater Sci Mater Med expected that in a near future advances in 2008; 19:1503-13; PMID:18266084; http://dx.doi. 25. Martin R A, Yne S, Hanna JV, Lee PD, Newport RJ, the fabrication techniques and develop- org/10.1007/s10856-008-3390-9 Smith ME, Jones JR. Characterizing the hierarchi- ment of 3D structures will provide scaf- 11. Bidan CM, Kommareddy KP, Rumpler M, cal structures of bioactive sol-gel silicate glass and hybrid scaffolds for bone regeneration. Philos Transct Kollmannsberger P, Fratzl P, Dunlop JW. Geometry folds that allow a better replica of the in as a factor for tissue growth: towards shape optimi- A Math Phys Eng Sci 2012; 370:1422-43; http:// vivo milieu. Having templates that bet- dx.doi.org/10.1098/rsta.2011.0308 zation of tissue engineering scaffolds. 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Effect of MO, Herzyk P, Wilkinson CDW, Oreffo ROC. The control of human mesenchymal cell differentiation electrospun fiber diameter and alignment on mac- No potential conflicts of interest were rophage activation and secretion of proinflamma- using nanoscale symmetry and disorder. Nat Mater 2007; 6:997-1003; PMID:17891143; http://dx.doi. tory cytokines and chemokines. Biomacromolecules disclosed. org/10.1038/nmat2013 2011; 12:1900-11; PMID:21417396; http://dx.doi. org/10.1021/bm200248h 28. McMurray RJ, Gadegaard N, Tsimbouri PM, Acknowledgments Burgess KV, McNamara LE, Tare R, Murawski K, 14. Hollister SJ, Murphy WL. Scaffold translation: bar- Kingham E, Oreffo ROC, Dalby MJ. Nanoscale sur- riers between concept and clinic. Tissue Eng Part We thank the Spanish MINECO for faces for the long-term maintenance of mesenchymal B Rev 2011; 17:459-74; PMID:21902613; http:// funding MN through the Ramón y Cajal stem cell phenotype and multipotency. Nat Mater dx.doi.org/10.1089/ten.teb.2011.0251 2011; 10:637-44; PMID:21765399; http://dx.doi. program and for funding TS through the 15. Yoshida M, Langer R, Lendlein A, Lahann J. From org/10.1038/nmat3058 advanced biomedical coatings to multi-functional- “Personal Técnico de Apoyo” subprogram. 29. Fong EL, Lamhamedi-Cherradi SE, Burdett E, ized biomaterials. Pol Rev 2006 ; 46:347-75 Ramamoorthy V, Lazar AJ, Kasper FK, Farach- 16. Kim JE, Lee EJ, Kim HE, Koh YH, Jang JH. The References Carson MC, Vishwamitra D, Demicco EG, Menegaz impact of immobilization of BMP-2 on PDO mem- BA, et al. Modeling Ewing sarcoma tumors in 1. Hollister SJ. Porous scaffold design for tissue engineer- brane for bone regeneration. J Biomed Mater Res A vitro with 3D scaffolds. Proc Natl Acad Sci U S A 2012 ; 100 :1488-93; PMID:22396132; http://dx.doi. ing. 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3D printed PLA-based scaffolds

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Taylor & Francis
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Copyright © 2013 Landes Bioscience
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Abstract

Views a ND COmmeNtary Views a ND COmmeNtary Organogenesis 9:4, 239–244; October/November/December 2013; © 2013 Landes Bioscience A versatile tool in regenerative medicine 1,2 1,2 1,2,3 1,2, Tiziano Serra , Miguel A Mateos-Timoneda , Josep A Planell , and Melba Navarro * 1 2 Institute for Bioengineering of Catalonia (IBEC); Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Barcelona, Spain; Technical University of Catalonia (UPC); Barcelona, Spain apid prototyping (RP), also known Rapid prototyping (RP) has become part Ras additive manufacturing (AM), of the set of techniques currently used in has been well received and adopted in the development of new implants and 3D 1– 4 the biomedical field. The capacity of this scaffolds for tissue engineering. Owing family of techniques to fabricate custom- to their capacity to build custom-made ized 3D structures with complex geom- 3D structures, RP techniques have arisen etries and excellent reproducibility has special interest within the regenerative revolutionized implantology and regen- medicine community. In addition to revo- erative medicine. In particular, nozzle- lutionize implantology and regenerative based systems allow the fabrication of therapies by introducing new possibilities high-resolution polylactic acid (PLA) to reconstruct and regenerate tissues in a structures that are of interest in regen- patient-specific manner, RP also provides erative medicine. These 3D structures a tremendous tool to fabricate scaffolds find interesting applications in the regen - on demand to obtain in vitro platforms erative medicine field where promising for studying the effect of various param- applications including biodegradable eters such as scaffolds architecture, pore templates for tissue regeneration pur- size, geometry, topography, wettability, poses, 3D in vitro platforms for study- and mechanical properties among others, ing cell response to different scaffolds on cells behavior including inflammatory conditions and for drug screening are response. considered among others. Scaffolds func- Within the additive manufacturing tionality depends not only on the fabrica- techniques family, nozzle-deposition- Keywords: scaffolds, polylactic acid tion technique, but also on the material based ones have shown great versatility. (PLA), tissue engineering, rapid proto- used to build the 3D structure, the geom- The approach consisting in a controlled typing, biodegradable, drug screening, etry and inner architecture of the struc- dispensing system integrated with pump- 3D in vitro culture system, regenerative ture, and the final surface properties. All ing technology and a CAD/CAM system medicine, composite material, calcium being crucial parameters affecting scaf- allows the precise and reproducible fabri- phosphate glass folds success. This Commentary empha- cation of 3D structures with well-defined Submitted: 05/14/13 sizes the importance of these parameters predetermined geometries. In particu- Revised: 08/01/13 in scaffolds’ fabrication and also draws lar, the use of this technique to fabricate the attention toward the versatility of “high-resolution” polylactic acid (PLA) Accepted: 08/04/13 these PLA scaffolds as a potential tool in 3D structures has been recently reported http://dx.doi.org/10.4161/org.26048 regenerative medicine and other medical by us. In that work we describe the fab- *Correspondence to: Melba Navarro; fields. rication of PLA based scaffolds with dif- Email: [email protected] ferent geometries and provide valuable Introduction information on the importance of the dif- Commentary to: Serra T, Planell JA, Navarro M. ferent fabrication parameters on both bulk High-resolution PLA-based composite scaffolds Additive manufacturing techniques have and surface properties, and their impact via 3-D printing technology. Acta Biomater 2013; 9:5521-30; PMID:23142224; http://dx.doi. been welcome in the biomaterials field. on cell adhesion. In brief, both PLA and org/10.1016/j.actbio.2012.10.041 This family of techniques also known as PLA/glass scaffolds were 3D-printed www.landesbioscience.com Organogenesis 239 ©2013 Landes Bioscience. Do not distribute. Figure 1. sem images of biodegradable 3D structures with various materials, geometries and architectures, (A) PLa /CaP glass composite orthogonal structure; (B) PLa tubular hexagonal mesh; (C and F) Chitosan orthogonal-diagonal structure; (D) PLa orthogonal-displaced structure, (E) PLa hexago- nal mesh. using the nozzle-deposition-based system and architecture of the final structure, must be carefully tuned in order to obtain (Tissue Engineering 3-Dn-300, Sciperio/ and (3) surface properties of the scaffolds. such structures. However, if a completely nScrypt Inc., available in the Rapid different material such as a hydrogel or Prototyping service of the Biomedical Importance of Materials a PLA/glass composite material is used, Networking Center, CIBER-BBN, and in 3D Printing results are completely different. This is IBEC www.ibecbarcelona.eu/biomateri- the case of chitosan scaffolds, chitosan is a ls). Homogeneous polymer a nd polymer/ Choosing the right material is crucial a natural hydrogel that requires in situ glass solutions in chloroform (5% w/v) to achieve functional 3D structures. cross-linking to keep the scaffold struc- were prepared and printed at 3mm/s and Materials’ intrinsic properties may affect tural integrity. Moreover, chitosan swells a pressure between 40–80 psi, through both surface and bulk properties of the when in contact with aqueous media. a G27 (200 μm) nozzle. Structures final structure. Moreover, materials’ prop - Thus, structures with significantly larger with two different architectures were erties have a direct effect on the attainment struts diameter than the pre-defined ones fabricated: (1) orthogonal structures of certain predetermined geometries. All are obtained. (Fig. 1A) with distance between struts these aspects affect the mechanical prop- In the case of composite materials such axes (~500 μm) and struts diameter erties and the overall performance of the as PLA/glass particles, though the over- around ~70 μm, and (2) displaced dou- 3D scaffold. all structural results are the same as with ble-layer structures (Fig. 1D) with a dis- In the case of PLA, processing with the PLA, the increase of viscosity due to the tance between struts axes of ~250 μm already mentioned 3D printing tool allows addition of glass particles in the print- and two layers dispensed in each direc- obtaining highly precise structures with ing solution implies some changes in the tion. Structural, mechanical and surface better resolution than the ones obtained printing parameters and the morphology 6,7 properties of the developed scaffolds were with other currently used methods. of the final structures. Furthermore, from studied as well as in vitro cell adhesion. This improvement in resolution is due the morphological point of view, incor- Results shown in that work illustrate to a particular interplay between a set of poration of glass particles in the polymer and highlight the significance of factors temperature/plastiziser/printing param- matrix has a significant effect on surface such as: (1) the material used to fabri- eters and the post-processing shrinkage of topography. In addition, the presence of cate the 3D structure, (2) the geometry the struts due to solvent evaporation that glass particles in the scaffold affects the 240 Organogenesis Volume 9 issue 4 ©2013 Landes Bioscience. Do not distribute. mechanical behavior of the structure and on the compressive modulus of both scaf- wettability, surface electrical charges, and 8,9 its degradation rate. folds (E In fact, when 50% = 93.32 ± 2.18; E = free energy are also changed. As a result, orthogonal displaced of glass particles (<40 μm) are blended in 28.38 ± 3.99MPa; n = 3) as described by the affinity of some proteins and cellu- the polymer solution, the elastic modulus us. Thus, depending on the mechanical lar response for a particular substrate is of the structures increases substantially requirements of the final application, the altered. Nowadays, different techniques (PLA = 28.38 ± 3.99 MPa, PLA/glass = right material/design combination has to aimed to modify scaffolds’ surface have 5 15–18 44.19 ± 2.67 MPa; n = 3). Therefore, it be chosen in order to get the most ade- been developed, among them surface is clear that materials’ properties have to quated structures. functionalization with proteins or peptide be carefully considered since each material Additionally to struts’ orientation and sequences as well as the incorporation of requires different and specific processing conformation, struts’ thickness plays an an inorganic bioactive phase that triggers conditions, and each material leads to dif- important role. Thinner rods contrib- specific cell events have been successfully ferent structures. ute to increasing the specific area of the achieved. scaffolds considerably and therefore the Surface functionalization with bio- Design and Architecture contact area between material and cells active molecules. Coupling functional of 3D Scaffolds increases. However, diminishing struts groups, or specific biomolecules such as diameter implies that the number of f unctiona l peptides to the surface by mea ns Design and inner architecture of the 3D rods required to build a specific volume of chemical treatments is one the most structure strongly depends on its final increases and therefore longer fabrication currently studied methods for improving application; in this sense, a wide variety times are required. Nonetheless, higher biomaterials bioactivity. In this context, of geometries can be developed as the scaffolds resolution is a valuable asset as surface functionalization of the already ones depicted in Figure 1. An important pointed by Hollister et al. who stated mentioned PL A 3D printed scaffolds with parameter affecting cell response is the that one of the technical constraints of collagen has been investigated. Both, phy- scaffold geometry including pores size, currently used solid free form techniques sisorbed and covalently bonded collagen shape, and struts size and orientation in order to fulfil scaffolds translation to surface coatings have been achieved. In among others. Scaffolds architecture not clinic is their limitation in terms of feature the case of physical absorption, the scaf- only affects their mechanical performance size resolution to the hundreds of micron folds were directly immersed in a solution but also affects their permeability, nutri- scale. Albeit this is the case in most of containing collagen, whereas to achieve ents diffusion and cell response. Indeed, the work published in this area, the work covalent bonding the surface was previ- it has been reported that mesenchymal reported by us reveals that high resolution ously treated with NaOH + EDC /NHS in stem cells (MSCs) differentiation and pro- structures with features below the hun- order to activate the accessible functional liferation of pre-osteoblastic cells is highly dreds of microns are possible with nozzle- groups and subsequently immersed in affected by the geometry of individual based printing technology. the collagen solution (100 μg/ml in PBS, 11,12 pores within the scaffold. 24 h at room temperature). Both types Also, it has been published that the Enhancing Cell Response of samples were evaluated and character- separation between struts as well as by Controlling Surface Properties ized by CBQCA and Micro BCA assays the morphology of pores and the angle to evaluate the amount and distribution formed between struts affect macro- Overall, the success of a biomaterial of the biomolecule on the surface of the phages reponse. In fact, we have recently strongly depends on its interaction with scaffolds. The experiment was performed confirmed that the variation of scaffold the biological environment. There are in triplicate. As observed in Figure 2, geometry from an orthogonal configura - applications where a direct and tight con- fully and homogeneously collagen cov- tion (squared pores) to a diagonal con- tact between the tissue and the material ered scaffolds were obtained (Fig. 2A). figuration (triangular pores) (see Fig. 1 ) is required while there are other applica- In addition, a higher protein density was affects both macrophages morphology tions where a rather antifouling behavior quantified on the covalently function - and cytokine expression (data not shown). is needed. Hence, it is clear that bioma- alized scaffolds (Fig. 2C). Also, a cell Furthermore, orthogonal scaffolds pro- terials surfaces are crucial to enhance and viability assay was performed to measure moted the presence of rounded multinu- control the biological response of scaffolds cell adhesion on both non-functionalized cleated giant cells, whereas diagonal ones and implantable devices. Both surface and functionalized (covalently attached lead to elongated macrophages. chemistry and surface topography are the collagen) scaffolds. Mesenchymal stem Moreover, the distribution of struts most important features affecting bioma- cells (3 × 10 cells/scaffold) were seeded and their thickness may also affect sig- terials biological response. in the scaffolds, polystyrene microplate nificantly on the mechanical properties of Modification of surface chemistry is wells were used as control. Cell adhesion the final scaffolds. As a matter of fact, it the most direct way to inu fl ence protein was studied at 4 and 24 h using a LDH has been shown that by modifying scaf- adsorption and therefore cell behavior. By assay kit. Results shown in Figure 2D are folds geometry from an orthogonal design tailoring functional groups available at the expressed as the average absorbance levels to a displaced or shifted one (Fig. 1A material surface it is possible to modify its of three samples (Fig. 2D). An ANOVA and D), there is a substantial variation surface properties, and consequently its analysis was performed to establish www.landesbioscience.com Organogenesis 241 ©2013 Landes Bioscience. Do not distribute. Figure 2. s urface functionalization of PLa 3D scaffolds: ( A) Fully and homogeneously collagen covered scaffold; ( B) rms Cs cultured on the functional- ized scaffolds after 72 h; ( C) Quantification of the amount of collagen on the scaffolds surface. Covalently functionalized scaffolds showed a signifi- cantly higher protein density than physisorbed ones; (D) LDH assay of adhered rms Cs after 4 and 24h of culture on both covalently- and non-function- alized PLa scaffolds. Functionalized scaffolds showed a higher number of viable cells after 24h. t he values marked with asterisk (*) showed statistical significant differences ( P ≤ 0.05). possible statistical significant differences and spreading of cells on G5 glass parti- Addition of G5 particles into the 10,21 (P ≤ 0.05) in the absorbance values. Cell cles than in the polymer matrix. This polymer matrix introduced an interest- studies showed a positive cell response in soluble glass degrades along time while ing topography to the scaffold surface as the functionalized scaffolds. In fact, after releasing different ions to the surround- observed in Figure 3A and B. In addition, 72 h of culture, mesenchymal stem cells ing media. It has been demonstrated that the surface of the polymer struts showed were very well spread and completely cov- the presence of G5 glass particles not only micro and nanopores left by the evapora- ering the scaffold surface (Fig. 2B). increases cell attachment and spreading tion of the solvent (see Fig. 3C). Thus, the Improving surface bioactivity by add- but also triggers angiogenesis and bone final structures presented a combination 2+ ing inorganic particles. As previously formation owing the Ca release and stiff- of porosities and other topography features 22,23 mentioned, other method for modifying ness of the glass. Indeed, several stud- ranging from the macroscale due to the surface chemistry is by adding bioactive ies have demonstrated the relevant role pores initially designed to the micro and 24,25 inorganic particles to the PLA matrix. In of ions on tissue regeneration. Given nanoscale due to solvent evaporation and this line, addition of a soluble, bioactive that the glass particles incorporated into the presence of glass particles. According 19,20 CaP glass, known as G5, in particles the polymer scaffold are partially exposed to the interferometry results, the addition shape to reinforce and improve bioactivity in the surface, as demonstrated by an of glass particles significantly increased of PLA scaffolds has been explored. It is alizarin red assay (where only the calci- the average roughness (Sa) of the surface known that G5 glass is highly hydrophilic fied inorganic phase is stained in red color, in comparison to PLA (PLA = 117.72 ± (contact angle = 29.8°). Thus, addition Fig. 3D), their presence contribute both 60.50 nm, PLA/glass = 1003.89 ± 228.45 of G5 particles contributes to decrease to modify surface chemistry and surface nm; n = 9). It is known that both surface PLA contact angle. Previous studies have topography. micro and nanoporosity play important demonstrated a preferential attachment roles in protein adhesion and therefore 242 Organogenesis Volume 9 issue 4 ©2013 Landes Bioscience. Do not distribute. Figure 3. sem images of (A and B) PLa /CaP glass composite scaffolds showing glass distribution and glass/polymer interface, white arrows indicate glass particles; (C) s truts of a PLa scaffold showing the micro and nanoporosity left after solvent evaporation; ( D) PLa /CaP glass scaffold after a lizarin red staining. r ed colored areas denote the CaP inorganic phase indicating the glass particles exposed on the scaffold surface. on cell response. Surface nanoporos- their interaction is stronger. Thus, con- cells’ morphology when comparing both ity not only increases the contact surface trolled nanoporosity might play an impor- types of scaffolds. After 4 h, immunofluo - area between the material and biological tant role in biological interactions. rescence images showed well spread cells entities but also generates nanoscale topo- We reported on the results of rMSCs with extended cytoskeleton on the scaf- graphical cues affecting cell behavior. In response to PLA and PLA/CaP glass scaf- folds with CaP glass particles and rela- fact, enhancement of cell interaction due folds with similar architecture at short peri- tively rounded cells on the PLA scaffolds. 27,28 to nanotopography has been reported. ods of time. Cell viability (WST assay, n = Thus, the obtained results suggested clear Cells do not interact directly with bio- 3) and morphology (confocal microscopy early cell morphological differences due to materials, but with an absorbed protein observation upon nuclei and cytoskeleton topographical and chemical changes. layer that provides anchoring sequences to staining) were evaluated after 4 and 24 h cells. Protein adsorption is highly depen- of adhesion in contact with the materials. Conclusions dent on surface properties; in particular, Results revealed that although both mate- it is believed that since the dimensions of rials displayed similar cell viability results, Data reported by us is a glimpse that surface nanofeatures are closer to proteins, noteworthy differences were observed in opens new possibilities to produce novel www.landesbioscience.com Organogenesis 243 ©2013 Landes Bioscience. Do not distribute. 2. Hutmacher DW, Schantz JT, Lam CXF, Tan KC, 17. Miyagi Y, Chiu LL, Cimini M, Weisel RD, Radisic PLA scaffolds with finely tuned architec - Lim TC. State of the art and future directions of M, Li RK. Biodegradable collagen patch with cova- scaffold-based bone engineering from a biomaterials lently immobilized VEGF for myocardial repair. tures at a higher resolution than currently perspective. 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Effect of MO, Herzyk P, Wilkinson CDW, Oreffo ROC. The control of human mesenchymal cell differentiation electrospun fiber diameter and alignment on mac- No potential conflicts of interest were rophage activation and secretion of proinflamma- using nanoscale symmetry and disorder. Nat Mater 2007; 6:997-1003; PMID:17891143; http://dx.doi. tory cytokines and chemokines. Biomacromolecules disclosed. org/10.1038/nmat2013 2011; 12:1900-11; PMID:21417396; http://dx.doi. org/10.1021/bm200248h 28. McMurray RJ, Gadegaard N, Tsimbouri PM, Acknowledgments Burgess KV, McNamara LE, Tare R, Murawski K, 14. Hollister SJ, Murphy WL. Scaffold translation: bar- Kingham E, Oreffo ROC, Dalby MJ. Nanoscale sur- riers between concept and clinic. Tissue Eng Part We thank the Spanish MINECO for faces for the long-term maintenance of mesenchymal B Rev 2011; 17:459-74; PMID:21902613; http:// funding MN through the Ramón y Cajal stem cell phenotype and multipotency. 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Journal

Organogenesis – Taylor & Francis

Published: Oct 1, 2013

Keywords: scaffolds; polylactic acid (PLA); tissue engineering; rapid prototyping; biodegradable; drug screening; 3D in vitro culture system; regenerative medicine; composite material; calcium phosphate glass

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