化材四乙
49940083
賴冠廷
Contents lists available at ScienceDirect
Acta Biomaterialia
j o u rn a l h o me p a g e : w w w . e l s e v i e r . c o m / l o c a t e / a c t a b io ma t
Review
Current trends in the design of scaffolds for
computer-aided tissue engineering
S.M. Giannitelli a, D. Accoto b, M. Trombetta a, A. Rainer a,⇑
a
Tissue Engineering Laboratory, CIR – Center for Integrated Research, Università Campus Bio-Medico di Roma, via Alvaro del Portillo 21,
00128 Rome, Italy
b
Biomedical Robotics and Biomicrosystems Laboratory, CIR – Center for Integrated Research, Università Campus Bio-Medico di Roma, via
摘要
通過添加劑製造引進進步顯著改善，定制腳手架架構的能力，增強了微觀結構特
徵的控制。這導致了在創新支架設計的開發越來越大的興趣，作為見證者的研究
活動，致力於支架的拓撲特徵及其成果ing性能之間的關係的認識越來越多，為
了找到能夠架構常常相互矛盾的要求（如生物和機械的）之間的最佳折衷。本文
的主要目的是提供一個檢討，並提出以解決關鍵問題，並在破譯設計標準以及由
此產生的SCAF倍性能之間的複雜聯繫幫助現有方法的支架設計和優化的分類。
簡介
在過去的十年中，組織工程（TE ）已經從添加劑的開發製造（ AM ）技術，
這導致了生產的自由形式與自定義定制架構多孔支架中受益。根據最新的ASTM
標準， AM可被定義為'接合材料從三維（ 3-D）模型數據製作的對象，通常層
層疊疊，而不是相減的製造方法的工序'' [ 1] 。從一個3 - D擋去除材料未像傳統
的減法過程，添加劑製造建立的最後一塊通過添加材料層，從一個三維計算機模
型開始。的3-D模型的'' ''切片成二維（ 2-D）層，其被轉讓給AM裝置的最終對
象的製造。用來冷杉，美食組織工程支架的應用市售AM技術包括：選擇性激光
燒結（SLS ） ，光固化（ SLA ） ，熔融沉積成型（FDM ），精密擠出沉積
（ PED）和三維印刷（ 3DP ） 。工作PRIN - ciples ，最近的趨勢和這些技術
目前的限制的詳細說明，已經由幾個顯著的綜述文章[ 2-4 ]提供。
其中一個主要的障礙，調幅的TE中的擴散已久的一套生物材料的限制，可以直
接加工來表示。然而，在印刷Technologies的，隨著新型複合生物材料的合成在
一起的最新進展，已經啟用了各種支架與定義形狀的製造和體外行為控制
[ 5 ] 。在這方面，親cessing水凝膠可以被認為是主要的挑戰，因為這些材料在
沉積過程使電池封裝，因此較吸引人的候選軟組織工程規劃應用程序在多個生物
材料，細胞的控制空間分佈和生物活性分子[6]是需要細胞外基質（ECM）的更
精確的模仿和更自然癒合過程。
加上添加劑製造的擴散，一務範式轉向計算機輔助組織工程（ CATE ）發生
[ 7 ] 。利用先進的影像工具，可重複的支架的設計和製造，擁有所需的孔隙度，
孔隙形狀和機械性能，已經大大緩解。支架微觀結構在確定功能tionality組織工
程化構建體的，因此，新的，ly成年組織中的核心作用，已經指出。因此，在深
入了解的腳手架拓撲特徵的影響是人為因素 [ 8 ] 。微觀元素的精確工程，導致
支架具有增強體外行為對於那些使用傳統的製造方法，它允許只腳手架整體形態
特徵的控制製造，但不是它的微觀幾何。這種傳統的製造方法的實例包括成孔劑
浸出，氣體發泡和相分離的[ 9-11 ] 。由於內部架構極大地影響關鍵因素組織再
生，如營養擴散，細胞粘附和基質沉積，支架必須仔細去簽約，牢記具體案件機
械，大眾交通和生物的要求。然而，定制腳手架體系架構，以更好地滿足相互矛
盾的要求，如生物和機械的，仍然是一個具有挑戰性的問題。在這種情況下，在
使用有限元分析（FEA）矽片驗證在體外的減少和體內實驗的努方面發揮了重大
作用。此外，模擬結果的合理準確，在與實證檢驗對比，導致了近期提前換貨有
限元分析來預測工具的先驗結構優化。事實上，腳手架設計正在成為其中微架構
創建和完善的SIL-ICO的組織要求和製造工藝的限制的基礎上，越來越多的一個
迭代的過程。
策略
多年來，一個'試錯'的方法已被採納為VAL- IDATE腳手架微架構，與正在向體外
或體內結果的基礎上對現有的設計事後修改。在矽片的實驗提供了可能性根據需
要，以確定用於更換所需的結構的最合適的配置，以擴大在模擬範圍內的設計參
數的範圍和數量。文獻報導的幾種方法都致力於支架與特定主題的外部形狀和內
部錯綜複雜的體系結構的建模。在這些中，分析方法提供了結構參數和機械性能
之間的經驗關係的手段全球機械行為的估計。最近的研究利用有限元分析，以便
根據具體要求來修改結構參數的事後調查支架性能。調幅過程，要求要製造的支
架的精確數字表示的產生，賦予一個天真的接口FEA環境中。特別是， CAD設
計可以提供的支架形態在微觀層面的精確輸入模式。操作方法以往，相加製造對
象及其預期設計的最終形狀之間的差異的影響 - 由於從製造工藝（表面粗糙
度，微孔等）所產生的問題 - 仍然知之甚少[ 92,93 ] 。其結果是，一些作者已
經選擇了應用FEA到的加法製造支架LCT重建，而不是依靠自己的CAD模型
[ 94,95 ] 。儘管對基於CAD建模精度的地位去大怒，合理的協定與實驗結果已經
證實了數相加多孔支架材料製造的[ 43,96 ] 。 FEA已經成功地用於AM聚合物的
力學性能和複合支架的預測。與實驗測試好協議，在由SLS製造PCL/hydroxyapa磷灰石支架的情況下被發現幾種計算研究都集中在determin - ING孔隙拓撲結構
上所產生的力學性能關係的影響，而只有少數人試圖提供一個更深入的了解孔結
構是如何影響的失效機制[ 98 ] 。加成盟友，孔結構對質量傳輸性能，進而影響
細胞活力，增殖和， ULTI - mately ，整體組織再生產生深遠的影響。因此，支
架的質量輸運特性的準確和高效的預測將是一個有效的腳手架工程過程[ 99 ]重
要的。與機械性能，生理值可以被視為一個起點，用於定義設計目標[100] 。另
外，在這種情況下，計算方法已經集成經驗評估，其目的在於提供一種更加嚴格
的方法來確定調幅棚架質量傳輸特性。
只要擴散而言，AM支架可以在有效擴散率，它是孔隙度參數（孔體積分數，孔
隙濃度strictivity和曲折度）的函數來描述。 FEA的應用，有效擴散係數的計算
調幅支架提供了一個更嚴格的方法來測定氧和營養物的擴散作為支架材料微觀
結構的函數，具體表現為Jung等人，計算SEV有效擴散係數誰 - ERAL上午腳手
架幾何尺寸與不同的內部多孔圖案。阿爾梅達和巴托羅最近開發出一種創新工具
結合基於CAD建模和拓撲優化，提供了一個先驗控制的機械屬性一的孔隙率和
支架結構的功能。而不是從預定義的單元電池開始的，該工具從材料的緻密無孔
的塊開始，根據孔隙度和剛度要求，目尋找一個拓撲OPTI- mized支架單元。在
腳手架優化方面取得進一步進展，負載適應性支架architecturing （ LASA ）算
法已經被提出，與支架設計的微架構是拓撲優化的機械性能為特定的載荷和邊界
條件方面的目的。而不是考慮填充有多孔結構和試圖優化的重複單元電池的設計
領域， LASA方法從緻密連續的實體模型，並生成一個小梁體系結構，通過考
慮那些ered體積[內工程材料安排114] 。在圖4 ，據報導LASA算法的示意圖。
結論
由於在上一節中，腳手架設計crite河口對整體組織再生出走過了顯著影響，並且
需要優化策略往往相互衝突的要求之間進行折衷。
繼CATE的擴散，策略pursu - ing一個最佳的支架設計，為特定臨床應用的數量大
大增加。通過集成的經驗，實驗室，計算機建模與仿真為基礎的活動，凱特有所
緩和支架為基礎的TE的提前一個多學科的研究領域。特別是，實驗分析和數值
模擬的組合導致了一種更有效的方法來開發的支架尋址目標要求，並已使一些新
穎的設計原則融入了評價仿生和生物功能集成到相同的體系結構的探索。
儘管一些總的趨勢可以得出，顯著重新搜索工作之前，了解所有規格而對生物學
通報腳手架的設計仍然是必要的。在最後幾年裡，只有少數的開發設計標準已在
腳手架生產中實施。此外，在體外和體內表徵廣泛的結果被限制到一個重新嚴格
許多組織和體系結構。空間填充曲線，用正交或蜂窩狀圖案，連同圖像為基礎的
設計，是最廣泛使用和字符，terized方法。相反，不規則的多孔結構，儘管似乎
更符合自然組織的複雜性，都沒有得到徹底地驗證。 TPMS設計的實施，最近
提供了令人鼓舞的初步結果，但需要進一步努力，以證明這種方法易學在體內設
置的全部潛力。
此外，硬和軟組織的應用程序之間的顯著間隙在進步，必須指出。事實上，在
CATE最顯著進展預期用於軟組織工程和器官再生。對於這些應用，新穎的CAD
模型和設計方法需要在不久的將來得到廣泛的探討。在這方面，雜交支架，集成
在同一個微結構的幾種材料的優點可以表現出更好的性能目標多組織或複雜器
官的重建。然而，到目前為止，多材料支架的幾個數據方面， ING快速成型的
情況下，甚至是更少的作品整合材料的選擇在腳手架微架構功能的有限元分析預
測。
另一個有趣的趨勢，被報告的擔憂積分的調幅技術，與其他支架的製造方法獲得
混合體系結構具有互補結構的有限元分析，Tures的。雖然這種創新的方法仍然
是在它的開始，它已經開始給予積極的成果不僅在複雜的組織中再演，而且在生
物過程，如血管結構的提升。
參考文獻
[1] ASTM International. ASTM F2792-10: standard terminology for additive manufacturing technologies. West Conshohocken, PA:
ASTM International; 2010.
[2] Melchels FPW, Domingos MAN, Klein TJ, Malda J, Bartolo PJS, Hutmacher DW. Additive manufacturing of tissues and organs. Prog
Polym
Sci 2012;37:1079–104.
[3] Bártolo PJS, Almeida H, Laoui T. Rapid prototyping and manufacturing for
tissue
engineering
scaffolds.
Int
J
Comput
Appl
2009;36:1–9.
[4] Peltola SM, Melchels FPW, Grijpma DW, Kellomäki M. A review of rapid prototyping techniques for tissue engineering
purposes. Ann Med 2008;40:268–80.
[5] Seol Y-J, Kang T-Y, Cho D-W. Solid freeform fabrication technology applied to tissue engineering
with various biomaterials. Soft
Matter 2012;8:1730–5.
[6]
Billiet T, Vandenhaute M, Schelfhout J, Van Vlierberghe S, Dubruel P. A review
of
trends
and
limitations
in
hydrogel-rapid
prototyping
for
tissue engineering. Biomaterials
2012;33:6020–41.
[7] Sun W, Darling A, Starly B, Nam J. Computer-aided tissue engineering: overview, scope and challenges. Biotechnol Appl Biochem
2004;39:29–47.
[8] Bohner M, Loosli Y, Baroud G, Lacroix D. Commentary: deciphering the link
between architecture and biological response of a bone graft substitute. Acta Biomater 2011;7:478–84.
[9] Sun Y, Finne-Wistrand A, Finne-Wistrand A, Albertsson PDA, Xing Z, Mustafa K, Hendrikson WJ, et al. Degradable amorphous
scaffolds with enhanced mechanical properties and homogeneous cell distribution produced by a three-dimension fiber deposition
method. J Biomed Mater Res A 2012;100A:2739–49.
[10] Melchels FPW, Barradas AMC, van Blitterswijk CA, de Boer J, Feijen J, Grijpma DW. Effects of
engineering
scaffolds on
cell
seeding
and
culturing.
Acta
Biomater
the
architecture
of
tissue
2010;6:4208–17.
[11] Lee K-W, Wang S, Dadsetan M, Yaszemski MJ, Lu L. Enhanced cell ingrowth and proliferation through three-dimensional
nanocomposite scaffolds with controlled
pore
structures.
Biomacromolecules
2010;11:682–9.
[12] Hutmacher DW, Sittinger M, Risbud MV. Scaffold-based tissue engineering: rationale for computer-aided design and solid
free-form fabrication systems. Trends Biotechnol 2004;22:354–62.
[13] Francoise M, Karoly J, Chirag K, Benjamin S, Scott D, Bradley H, et al. Toward engineering functional organ modules by additive
manufacturing. Biofabrication
[14]
2012;4:022001.
Sun W, Lal P. Recent development on computer aided tissue engineering — a
review. Comput Methods Programs Biomed 2002;67:85–103.
[15] Sun W, Starly B, Darling A, Gomez C. Computer-aided tissue engineering: application to biomimetic modelling and design of
tissue scaffolds. Biotechnol Appl Biochem 2004;39:49–58.
[16] Lacroix D, Planell JA, Prendergast PJ. Computer-aided design and finite- element modelling of biomaterial scaffolds for bone tissue
engineering. Phil Trans R Soc A 2009;367:1993–2009.
[17] Boccaccio A, Ballini A, Pappalettere C, Tullo D, Cantore
and
biomimetic
scaffolds in
bone
tissue
S,
Desiate
engineering.
A. Finite
Int
J
Biol
element
Sci
method
(FEM),
mechanobiology
2011;7:112–32.
[18] Sun W, Hu X. Reasoning Boolean operation based modeling for heterogeneous objects. Comput Aided Des 2002;34:481–8.
[19] Gabbrielli R, Turner IG, Bowen CR. Development of modelling methods for materials to be used as bone substitutes. Key Eng Mat
2008;361– 363(II):901–6.
[20] Chiu WK, Yeung YC, Yu KM. Toolpath generation for layer manufacturing of fractal
objects.
Rapid
Prototyping
J
2006;12:214–21.
[21] Duan B, Cheung WL, Wang M. Optimized fabrication of Ca-P/PHBV nanocomposite scaffolds via selective laser sintering for bone
tissue engineering.
[22]
Chantarapanich
Biofabrication
N,
2011;3:015001.
Puttawibul
P,
Sucharitpwatskul
library for tissue engineering: a geometric
evaluation.
S,
Jeamwatthanachai P, Inglam S, Sitthiseripratip K. Scaffold
Comput
Math
Methods
Med
2012;2012:14.
[23] Wettergreen MA, Bucklen BS, Starly B, Yuksel E, Sun W, Liebschner MAK.
Creation of a unit block library of architectures for use in assembled scaffold engineering. Comput Aided Design
2005;37:1141–9.
[24] Chua CK, Leong KF, Cheah CM, Chua SW. Development of a tissue engineering scaffold structure library for rapid prototyping. Part 1:
Investigation and classification.
Int
J
Adv
Manuf
Tech
2003;21:291–301.
[25] Cheah CM, Chua CK, Leong KF, Chua SW. Development of a tissue engineering scaffold structure library for rapid prototyping. Part 2:
Parametric library and assembly
program.
Int
J
Adv
Manuf
Tech
2003;21:302–12.
[26] Cheah CM, Chua CK, Leong KF, Cheong CH, Naing MW. Automatic algorithm for generating complex polyhedral scaffolds for
tissue
[27]
engineering.
Tissue Eng
2004;10:595–610.
Naing MW, Chua CK, Leong KF, Wang Y. Fabrication of customised scaffolds
using
computer-aided
design
and
rapid
prototyping
techniques.
Rapid Prototyping
J
2005;11:249–59.
[28] Sudarmadji N, Tan JY, Leong KF, Chua CK, Loh YT. Investigation of the mechanical properties and porosity relationships in
selective laser-sintered polyhedral for functionally graded scaffolds. Acta Biomater 2011;7:530–7.
[29] Sun W, Starly B, Nam J, Darling A. Bio-CAD modeling and its applications in computer-aided
tissue engineering. Comput Aided
Design 2005;37:1097–114.
[30] Bucklen BS, Wettergreen WA, Yuksel E, Liebschner MAK. Bone-derived CAD library for assembly of scaffolds in computer-aided
tissue engineering. Virtual Phys Prototyp 2008;3:13–23.
[31] Nam J, Starly B, Darling A, Sun W. Computer aided tissue engineering for
modeling and design of novel tissue scaffolds. Computer-Aided Design & Applications 2004;1:633–40.
[32] Hollister SJ, Levy RA, Chu T-M, Halloran JW, Feinberg SE. An image-based approach for designing and manufacturing craniofacial
scaffolds.
Int
J
Oral Max
Surg
2000;29:67–71.
[33] Feinberg SE, Hollister SJ, Halloran JW, Chu TMG, Krebsbach PH. Image-based biomimetic approach to reconstruction of the
temporomandibular joint. Cells Tissues
[34] Smith
MH,
Flanagan
Computed
CL,
Organs
Kemppainen
tomography-based
2001;169:309–21.
JM,
Sack JA,
Chung
tissue-engineered
H,
Das
scaffolds
S,
et
al.
in craniomaxillofacial surgery. Int J Med Robot Comp
2007;3:207–16.
[35] Hollister
SJ,
scaffolds
to
Maddox
RD,
Taboas
mimic
tissue
JM.
Optimal
properties
and
design
satisfy
and
fabrication
biological
of
constraints. Biomaterials 2002;23:4095–103.
[36] Hollister SJ. Porous scaffold design for tissue engineering. Nat Mater 2005;4:518–24.
[37] Pasko
A,
Fryazinov
function-based
O,
modelling
Vilbrandt
of
T,
Fayolle
volumetric
P-A,
Adzhiev
microstructures.
V.
Graph
Procedural
Models 2011;73:165–81.
[38] Kapfer SC, Hyde ST, Mecke K, Arns CH, Schröder-Turk GE. Minimal surface scaffold designs for tissue engineering. Biomaterials
2011;32:6875–82.
[39] Rajagopalan S, Robb RA. Schwarz meets Schwann: design and fabrication of
biomorphic and durataxic tissue engineering scaffolds. Med Image Anal 2006;10:693–712.
[40] Seck TM, Melchels FPW, Feijen J, Grijpma DW. Designed biodegradable hydrogel structures prepared by stereolithography using
poly(ethylene glycol)/poly(D,
L-lactide)-based
resins.
J
Control
Release
2010;148:34–41.
[41] Melchels FPW, Feijen J, Grijpma DW. A poly(d, l-lactide) resin for the preparation of tissue engineering scaffolds by
stereolithography. Biomaterials 2009;30:3801–9.
[42] Elomaa L, Teixeira S, Hakala R, Korhonen H, Grijpma DW, Seppälä JV. Preparation of poly(e-caprolactone)-based tissue
engineering scaffolds by stereolithography.
Acta
Biomater
2011;7:3850–6.
[43] Melchels FPW, Bertoldi K, Gabbrielli R, Velders AH, Feijen J, Grijpma DW. Mathematically defined tissue engineering scaffold
architectures prepared by stereolithography.
[44]
Biomaterials
2010;31:6909–16.
Olivares AL, Marsal E, Planell JA, Lacroix D. Finite element study of scaffold
architecture design and culture conditions for tissue engineering. Biomaterials 2009;30:6142–9.
[45] Yoo D-J. Computer-aided porous
Precis
Eng
Man
scaffold design
for tissue
engineering using triply
periodic
minimal
surfaces.
Int
J
2011;12:61–71.
[46] Yoo D-J. Porous scaffold design using the distance field and triply periodic minimal surface models. Biomaterials
2011;32:7741–54.
[47]
Hoque ME, Chuan YL, Pashby I. Extrusion based rapid prototyping technique:
An advanced platform for tissue engineering scaffold fabrication. Biopolymers 2012;97:83–93.
[48] Zein I, Hutmacher DW, Tan KC, Teoh SH. Fused deposition modeling of novel scaffold architectures for tissue engineering
applications. Biomaterials 2002;23:1169–85.
[49] Woodfield TBF, Moroni L, Malda J. Combinatorial approaches to controlling cell behaviour and
tissue formation
in
3D
via
rapid-prototyping and smart scaffold design. Comb Chem High T Scr 2009;12:562–79.
[50] Li JP, de Wijn JR, van Blitterswijk CA, de Groot K. The effect of scaffold architecture on properties of direct 3D fiber deposition of
porous Ti6Al4V for orthopedic
implants.
J
Biomed
Mater
Res
A
2010;92A:33–42.
[51] Woodfield TBF, Malda J, de Wijn J, Péters F, Riesle J, van Blitterswijk CA. Design of porous scaffolds for cartilage tissue
engineering using a three- dimensional
fiber-deposition
technique.
Biomaterials
2004;25:4149–61.
[52] Moroni L, de Wijn JR, van Blitterswijk CA. 3D fiber-deposited scaffolds for tissue engineering: Influence of pores geometry and
architecture on dynamic mechanical
properties.
Biomaterials
2006;27:974–85.
[53] Hutmacher DW, Schantz T, Zein I, Ng KW, Teoh SH, Tan KC. Mechanical properties and cell cultural response
scaffolds
designed and fabricated via
fused deposition modeling. J Biomed
of
polycaprolactone
Mater Res 2001;55:203–16.
[54] Tellis BC, Szivek JA, Bliss CL, Margolis DS, Vaidyanathan RK, Calvert P. Trabecular scaffolds created using micro CT guided
fused
deposition modeling. Mat Sci Eng C 2008;28:171–8.
[55] Lee JS, Cha HD, Shim JH, Jung JW, Kim JY, Cho DW. Effect of pore architecture and stacking direction on mechanical properties of
solid freeform fabrication- based scaffold for bone tissue engineering. J Biomed Mater Res A 2012;100:1846–53.
[56] Ahn S, Kim Y, Lee H, Kim G. A new hybrid scaffold constructed of solid freeform-fabricated PCL struts and collagen
bone
tissue
regeneration:
fabrication,
mechanical
properties,
and
cellular
activity.
J Mater
struts
for
Chem
2012;22:15901–9.
[57] Schuurman W, Khristov V, Pot MW, van Weeren PR, Dhert WJ, Malda J. Bioprinting of hybrid tissue constructs with tailorable
mechanical properties. Biofabrication
[58]
2011;3:021001.
Schantz J-T, Hutmacher DW, Lam CXF, Brinkmann M, Wong KM, Lim TC, et al.
Repair of calvarial defects with customised tissue-engineered bone grafts - II. Evaluation of cellular efficiency and efficacy in
vivo. Tissue Eng 2003;9:127–39.
[59] Shor L. Precision extruding deposition (PED) fabrication of polycaprolactone (PCL) scaffolds for bone tissue engineering.
Biofabrication 2009;1:015003.
[60] Sawyer AA, Song SJ, Susanto E, Chuan P, Lam CXF, Woodruff MA, et al. The stimulation of healing within a rat calvarial defect
by mPCL–TCP/collagen scaffolds loaded with rhBMP-2. Biomaterials 2009;30:2479–88.
[61] Lee CH, Cook JL, Mendelson A, Moioli EK, Yao H. J Mao J. Regeneration of the articular surface of the rabbit synovial joint by cell
homing: a proof of concept study.
Lancet
2010;376:440–8.
[62] Shao X, Goh JC, Hutmacher DW, Lee EH, Zigang G. Repair of large articular osteochondral defects using hybrid scaffolds and
bone marrow-derived mesenchymal stem cells in a rabbit model. Tissue Eng 2006;12:1539–51.
[63] Abbah SA, Lam CXF, Hutmacher DW, Goh JC, Wong HK. Biological performance of a polycaprolactone-based scaffold
as
fusion
cage device in a large animal model of spinal reconstructive surgery. Biomaterials
[64] Lee JW, Ahn G, Kim JY, Cho D-W. Evaluating cell proliferation
using solid freeform fabrication
[65] Sobral
JM,
Caridade
SG,
technology.
Sousa
RA,
J
Mater
Mano
JF,
based
2009;30:5086–93.
on internal pore size and 3D scaffold architecture fabricated
Sci-Mater
Reis
used
M
RL.
2010;21:3195–205.
Three-dimensional
plotted scaffolds with controlled pore size gradients: Effect of scaffold geometry on mechanical performance and cell seeding
efficiency. Acta Biomater 2011;7:1009–18.
[66] Sagan H. Space-Filling Curves. Berlin: Springer-Verlag; 1994.
[67] Starly B, Sun W. Internal scaffold architecture designs using lindenmayer systems. Computer-Aided Design and Applications
2007;4:395–403.
[68] Kumar GS, Pandithevan P, Ambatti AR. Fractal raster tool paths for layered
manufacturing of porous objects. Virtual Phys Prototyp 2009;4:91–104.
[69] Kou XY, Tan ST. A simple and effective geometric representation for irregular porous structure modeling. Computer Aided Design
2010;42:930–41.
[70]
Chen Y, Cadman J, Zhou S, Li Q. Computer-aided design and fabrication of biomimetic materials and scaffold micro-structures. Adv Mater Res 2011;213:628–32.
[71] Chen Z, Su Z, Ma S, Wu X, Luo Z. Biomimetic modeling and three-dimension reconstruction of the artificial bone. Comput meth prog
bio 2007;88:123–30.
[72] Leong KF, Chua CK, Sudarmadji N, Yeong Y. Engineering functionally graded
tissue
engineering
scaffolds.
J
Mech
Behav
Biomed
2008;1:140–52.
[73] Kalita SJ. Development of controlled porosity polymer-ceramic composite scaffolds via fused deposition modeling. Mat Sci and Eng C
2003;23:611–20.
[74] Khoda AKMB, Ozbolat IT, Koc B. Engineered tissue scaffolds with variational porous
architecture.
J
Biomech
Eng
2011;133:011001.
[75] Khoda AKMB, Ozbolat IT, Koc B. A functionally gradient variational porosity architecture
for hollowed scaffolds fabrication.
Biofabrication 2011;3:034106.
[76] Ozbolat IT, Koc B. A Continuous multi-material toolpath planning for tissue scaffolds with hollowed features. Computer-Aided
Design & Applications 2011;8:237–47.
[77] Ozbolat
IT,
Koc
B.
Multi-function
based
modeling
of
3D
heterogeneous
wound scaffolds for improved wound healing. Computer-Aided Design & Applications 2011;8:43–57.
[78] Pandithevan P, Saravana Kumar G. Personalised bone tissue engineering scaffold with controlled architecture using fractal tool
paths in layered manufacturing. Virtual Phys Prototyp 2009;4:165–80.
[79] Wettergreen M, Bucklen B, Liebschner M, Sun W. CAD assembly process for bone replacement scaffolds in computer-aided tissue
engineering. Virtual Prototyping & Bio Manufacturing in Medical Applications. Springer Verlag; 2008. p. 87–111.
[80] Wettergreen M, Bucklen B, Sun W, Liebschner M. Computer-aided tissue engineering of a human vertebral body. Ann Biomed Eng
2005;33:1333–43.
[81]
Kai H, Wang X, Madhukar KS, Qin L, Yan Y, Zhang R. Fabrication of a two-level
tumor bone repair biomaterial based on a rapid prototyping technique. Biofabrication 2009;1:025003.
[82] Kang HW, Park JH, Kang TY, Seol YJ, Cho DW. Unit cell-based computer-aided manufacturing
system for
tissue engineering.
Biofabrication 2012;4:015005.
[83]
Vaquette C, Fan W, Xiao Y, Hamlet S, Hutmacher DW, Ivanovski S. A biphasic
scaffold design combined with cell sheet technology for simultaneous regeneration of alveolar bone/periodontal ligament
complex. Biomaterials 2012;33:5560–73.
[84] Liu L, Xiong Z, Yan Y, Zhang R, Wang X, Jin L. Multinozzle low-temperature deposition system for construction of gradient tissue
engineering scaffolds. J Biomed Mater Res B 2009;88B:254–63.
[85] Schroeder C, Regli WC, Shokoufandeh A, Sun W. Computer-aided design of porous artifacts. Comput Aided Design
2005;37:339–53.
[86] Sogutlu S, Koc B. Stochastic modeling of tissue engineering scaffolds with
varying porosity levels. Computer-Aided Design & Applications 2007;4:661–70.
[87]
Lal
P,
Sun
W.
Computer
modeling
approach
for
microsphere-packed
bone
scaffold. Comput Aided Design 2004;36:487–97.
[88] Schaefer DW, Keefer KD. Structure of random porous materials: silica aerogel.
Phys Rev Lett 1986;56:2199–202.
[89] Kou XY, Tan ST. Microstructural modelling of functionally
representations. Int
J
Comput Integ
M
graded
materials using stochastic Voronoi diagram
and B-Spline
2011;25:177–88.
[90] Cai S, Xi J. A control approach for pore size distribution in the bone scaffold based on the hexahedral mesh refinement. Comput Aided
Design 2008;40:1040–50.
[91] Melchels FPW, Wiggenhauser PS, Warne D, Barry M, Ong FR, Chong WS, et al.
CAD/CAM-assisted breast reconstruction. Biofabrication 2011;3:034114.
element
predictions
compared
[92] Cahill
S,
Lohfeld
S,
McHugh
PE.
Finite
to
experimental results for the effective modulus of bone tissue engineering scaffolds fabricated by selective laser sintering. J
Mater Sci: Mater Med 2009;20:1255–62.
[93] Ryan G, McGarry P, Pandit A, Apatsidis D. Analysis of the mechanical behavior of a titanium scaffold with a repeating unit-cell
substructure. J Biomed Mater Res
B
2009;90B:894–906.
[94] Saito E, Kang H, Taboas J, Diggs A, Flanagan C, Hollister S. Experimental and computational characterization of
fabricated
50:50
PLGA porous scaffolds for
human
trabecular
bone
applications.
J
Mater
designed
and
Sci-Mater M
2010;21:2371–83.
[95] Williams JM, Adewunmi A, Schek RM, Flanagan CL, Krebsbacha PH, Feinberg SE, et al. Bone tissue engineering using
polycaprolactone scaffolds fabricated via selective laser sintering. Biomaterials 2005;26:4817–27.
[96]
Eshraghi S, Das S. Mechanical and microstructural properties of polycaprolactone
scaffolds with one-dimensional,
two-dimensional, and three-dimensional orthogonally oriented porous architectures produced by selective laser sintering. Acta
Biomater 2010;6:2467–76.
[97] Eshraghi S, Das S. Micromechanical finite-element modeling
and experimental characterization of the compressive mechanical
properties of polycaprolactone–hydroxyapatite composite scaffolds prepared by selective laser sintering for bone tissue engineering.
Acta Biomater 2012;8:3138–43.
[98] Amirkhani S, Bagheri R, Zehtab Yazdi A. Manipulating failure mechanism of rapid prototyped scaffolds by
connectivity
and
geometry
of the
pores.
J
Biomech
changing
nodal
2012;45:2866–75.
[99] Pennella F, Cerino G, Massai D, Gallo D, Falvo D’Urso Labate GVU, Schiavi A, et al. A survey of methods for the evaluation of
tissue engineering scaffold permeability. Ann Biomed Eng 2013:1–15.
[100] Hollister SJ. Scaffold design and manufacturing: from concept to clinic. Adv Mater 2009;21:3330–42.
[101] Woo Jung J, Yi H-G, Kang T-Y, Yong W-J, Jin S, Yun W-S, et al. Evaluation of the effective diffusivity of a freeform fabricated scaffold
using computational simulation.
[102]
J
Biomech
Eng
2013;135:084501.
Malda J, Woodfield TB, Van Der Vloodt F, Kooy F, Martens DE, Tramper J, et al.
The effect of PEGT/PBT scaffold architecture on oxygen gradients in tissue engineered cartilaginous constructs. Biomaterials
2004;25:5773–80.
[103] McCoy RJ, O’Brien FJ. Influence of shear stress in perfusion bioreactor cultures for the development of three-dimensional
bone
tissue constructs: a review. Tissue Engineering Part B 2010;16:587–601.
[104] Truscello S, Kerckhofs G, Van Bael S, Pyka G, Schrooten J, Van Oosterwyck H. Prediction of permeability of regular scaffolds for
skeletal tissue engineering: a combined computational and experimental study. Acta Biomater 2012;8:1648–58.
[105] Singh H, Teoh S-H, Low HT, Hutmacher DW. Flow modelling within a scaffold under the influence of uni-axial and bi-axial bioreactor
rotation.
J Biotechnol 2005;119:181–96.
[106] Hutmacher DW, Singh H. Computational fluid dynamics for improved bioreactor design and 3D culture. Trends Biotechnol
2008;26:166–72.
[107] Yan X, Chen X, Bergstrom D. Modeling of the flow within scaffolds in perfusion
bioreactors.
Am
J
Biomed
Eng
2011;1:72–7.
[108] Yao Y, Chen WD, Jin WY. The influence of pore structure on internal flow field shear stress within scaffold. Adv Mat Res
2011;308:771–5.
[109] Melchels FPW, Tonnarelli B, Olivares AL, Martin I, Lacroix D, Feijen J, et al. The influence of the scaffold design on the distribution
of adhering cells after perfusion
cell
seeding.
Biomaterials
2011;32:2878–84.
[110] Bendsøe MP, Sigmund O. Topology optimization: theory, methods,
[111] Lin CY. A
novel method for biomaterial scaffold internal architecture
and applications. London: Springer Verlag; 2003.
design to match bone elastic properties with desired porosity.
J
Biomech 2004;37:623–36.
[112] Challis VJ, Roberts AP, Grotowski JF, Zhang L-C, Sercombe TB. Prototypes for bone implant scaffolds designed via topology
optimization and manufactured by solid freeform fabrication. Adv Eng Mater 2010;12:1106–10.
[113] Almeida HD, Bártolo PJDS. Virtual topological optimisation of scaffolds for rapid prototyping. Med Eng Phys 2010;32:775–82.
[114]
Rainer A, Giannitelli SM, Accoto D, De Porcellinis S, Guglielmelli E, Trombetta
M. Load-adaptive scaffold architecturing: a bioinspired approach to the design of porous additively manufactured scaffolds
with optimized mechanical properties. Ann Biomed Eng 2012;40:966–75.
[115] Lam CXF, Savalani MM, Teoh SH, Hutmacher DW. Dynamics of in vitro polymer degradation of polycaprolactone-based
scaffolds: accelerated versus simulated physiological conditions. Biomed Mater 2008;3:034108.
[116] Saito E, Liu Y, Migneco F, Hollister SJ. Strut size and surface area effects on
long-term in vivo degradation in computer designed poly(L-lactic acid) three- dimensional porous scaffolds. Acta Biomater
2012;8:2568–77.
[117]
Heljak
Ś wie˛ szkowski
MK,
W, Lam
CXF,
Hutmacher
DW,
Kurzydłowski
Evolutionary design of bone scaffolds with reference to material selection. Int J
KJ.
Numer
Meth
[118] Adachi T. Framework for optimal design of porous scaffold microstructure by computational
Eng
2012;28:789–800.
simulation
of
bone
regeneration. Biomaterials 2006;27:3964–72.
[119] Erkizia G, Rainer A, De Juan-Pardo E, Aldazabal J. Computer simulation of scaffold
degradation.
J
Phys
Conf
Ser
2010;252:012004.
[120] Byrne DP, Lacroix D, Planell JA, Kelly DJ, Prendergast PJ. Simulation of tissue differentiation in a scaffold as a function of
porosity, Young’s modulus and dissolution rate: application of mechanobiological models in
tissue engineering.
Biomaterials
2007;28:5544–54.
[121] Checa S, Prendergast P. A mechanobiological model for tissue differentiation that includes angiogenesis: a lattice-based modeling
approach. Ann Biomed Eng
2009;37:129–45.
[122] Chen Y, Zhou S, Li Q. Microstructure design of biodegradable scaffold and its effect
on
tissue
regeneration.
Biomaterials
2011;32:5003–14.
[123] Malda J, Martens DE, Tramper J, van Blitterswijk CA, Riesle J. Cartilage tissue engineering: controversy in the effect of oxygen.
Critic Rev Biotechnol 2003;23:175–94.
[124] Karande TS, Ong JL, Agrawal CM. Diffusion in musculoskeletal tissue engineering scaffolds: design issues related to porosity,
permeability, architecture, and nutrient mixing. Ann Biomed Eng 2004;32:1728–43.
[125] Saha K, Pollock JF, Schaffer DV, Healy KE. Designing synthetic materials to control stem cell phenotype. Curr Opin Chem Biol
2007;11:381–7.
[126] Salem
A,
Stevens
Interactions
of 3T3
R,
Pearson
fibroblasts
and
R,
Davies
endothelial
M,
Tendler
cells
with
S,
Roberts
defined
C,
et
al.
pore features.
J
Biomed
Mater
2002;61:212–7.
[127]
Sun T, Norton D, Ryan A, MacNeil S, Haycock J. Investigation of fibroblast and
keratinocyte cell-scaffold interactions using a novel 3D cell culture system. J Mater
Sci
Mater
Med
2007;18:321–8.
Res
[128]
Forte
G,
Carotenuto
F,
Pagliari
F,
Pagliari
S,
Cossa
P,
Fiaccavento
R,
et
al.
Criticality of the biological and physical stimuli array inducing resident cardiac stem cell determination. Stem Cells
2008;26:2093–103.
[129] Kim K, Yeatts A, Dean D, Fisher JP. Stereolithographic bone scaffold design parameters: osteogenic differentiation and signal
expression. Tissue Eng 2010;16:523–39.
[130] Chu T-MG, Orton DG, Hollister SJ, Feinberg SE, Halloran JW. Mechanical and in vivo performance of hydroxyapatite implants with
controlled architectures.
Biomaterials
2002;23:1283–93.
[131] Yliperttula M, Chung BG, Navaladi A, Manbachi A, Urtti A. High-throughput screening of cell responses
to biomaterials. Eur J
Pharm Sci 2008;35:151–60.
[132] Sundelacruz S, Kaplan DL. Stem cell- and scaffold-based tissue engineering approaches to osteochondral regenerative medicine.
Semin Cell Dev Biol 2009;20:646–55.
[133] Cipitria A, Lange C, Schell H, Wagermaier W,
Reichert JC, Hutmacher DW, et al. Porous scaffold architecture guides tissue
formation. J Bone Miner Res 2012;27:1275–88.
[134] Lee J, Cuddihy MJ, Kotov NA. Three-dimensional cell culture matrices: state of the art. Tissue Eng 2008;14:61–86.
[135] Schantz J-T, Lim T-C, Ning C, Teoh SH, Tan KC, Wang SC, et al. Cranioplasty
after trephination using a novel biodegradable burr hole cover: technical case report. Neurosurgery 2006;58. ONS-E176.
[136] Hutmacher DW, Cool S. Concepts of scaffold-based tissue engineering—the
rationale
to
use
solid
free-form
fabrication
techniques.
J
Cell
Mol
[137] Rouwkema J, Rivron NC, van Blitterswijk CA. Vascularization in tissue engineering.
Med 2007;11:654–69.
Trends
Biotechnol
2008;26:434–41.
[138] Novosel EC, Kleinhans C, Kluger PJ. Vascularization is the key challenge in
tissue engineering. Adv Drug Deliver Rev 2011;63:300–11.
[139] Niino T, Hamajima D, Montagne K, Oizumi S, Naruke H, Huang H, et al. Laser sintering fabrication of three-dimensional tissue
engineering scaffolds with a flow channel network.
[140] H-s
Yun,
S-e
Kim,
mesoporous–giantporous
[141]
Y-t
Hyun,
S-j
inorganic/organic
Biofabrication 2011;3:034104.
Heo,
J-w
composite
Shin.
scaffolds
Three-dimensional
for
tissue engineering. Chem Mater 2007;19:6363–6.
Cesarano J, Dellinger JG, Saavedra MP, Gill DD, Jamison RD, Grosser BA, et al.
Customization
of
load-bearing
hydroxyapatite
lattice
scaffolds.
Int
J
Appl Ceram
Tec
2005;2:212–20.
[142] Taboas J, Maddox R, Krebsbach P, Hollister S. Indirect solid free form fabrication of local and global porous, biomimetic and composite
3D polymer-ceramic
scaffolds.
Biomaterials
2003;24:181–94.
[143] Peña J, Román J, Victoria Cabañas M, Vallet-Regí M. An alternative technique to shape scaffolds with hierarchical porosity at
physiological
temperature. Acta Biomater 2010;6:1288–96.
[144] Izadifar Z, Chen X, Kulyk W. Strategic design and fabrication of engineered
scaffolds
for
articular
cartilage
repair.
J
Funct
Biomater
2012;3:799–838. [145]
Woodfield T, Blitterswijk CV, Wijn JD,
Sims T, Hollander A, Riesle J. Polymer
scaffolds fabricated with pore-size gradients as a model for studying the
zonal organization within tissue-engineered cartilage constructs. Tissue Eng 2005;11:1297–311.
[146] Jeong CG, Hollister SJ. Mechanical and biochemical assessments of threedimensional poly (1, 8-octanediol-co-citrate) scaffold pore shape and permeability effects on in vitro chondrogenesis using
primary chondrocytes. Tissue Eng 2010;16:3759–68.
[147] Kock L, van Donkelaar CC, Ito K. Tissue engineering of functional articular cartilage: the current status. Cell Tissue Res
2012;347:613–27.
[148] Cao T, Ho K-H, Teoh S-H. Scaffold design and in vitro study of osteochondral coculture in a three-dimensional porous
polycaprolactone scaffold fabricated by fused deposition modeling. Tissue Eng 2003;9:103–12.
[149] Nooeaid P, Salih V, Beier JP, Boccaccini AR. Osteochondral tissue engineering: scaffolds,
Mol
Med
stem
cells
and
applications.
J
Cell
2012;16:2247–70.
[150] Schek RM, Taboas JM, Segvich SJ, Hollister SJ, Krebsbach PH. Engineered osteochondral grafts using biphasic composite solid
free-form fabricated scaffolds. Tissue Eng 2004;10:1376–85.
[151] Bian W, Li D, Lian Q, Li X, Zhang W, Wang K, et al. Fabrication of a bio-inspired beta-Tricalcium
on ceramic stereolithography
and
gel
casting
for
osteochondral
tissue
phosphate/collagen scaffold based
engineering. Rapid
Prototyping
J
2012;18:68–80.
[152] Fedorovich NE, Schuurman W, Wijnberg HM, Prins H-J, van Weeren PR, Malda J, et al. Biofabrication of osteochondral tissue
equivalents by printing topologically defined, cell-laden hydrogel scaffolds. Tissue Eng 2011;18:33–44.
[153] Mironov V, Kasyanov V, Drake C, Markwald RR. Organ printing: promises and challenges. Future Med 2008:93–103.
[154] Yeong W, Sudarmadji N, Yu H, Chua C, Leong K, Venkatraman S, et al. Porous
polycaprolactone
scaffold
for
cardiac
tissue
engineering
fabricated
by selective laser
sintering.
Acta Biomater
2010;6:2028–34.
[155]
Centola M, Rainer A, De Porcellinis S, Genovese JA, Trombetta M. Combining
electrospinning and fused deposition modeling for the fabrication of a hybrid vascular graft. Biofabrication 2010;2:014102.
[156] Park H, Larson BL, Guillemette MD, Jain SR, Hua C, Engelmayr Jr GC. The significance of pore microarchitecture in a
multi-layered elastomeric scaffold for
contractile
cardiac
muscle
constructs.
Biomaterials
2011;32:1856–64.
[157] Hockaday L, Kang K, Colangelo N, Cheung P, Duan B, Malone E, et al. Rapid 3D printing of anatomically accurate and mechanically
heterogeneous aortic valve hydrogel scaffolds. Biofabrication 2012;4:035005.
[158] Wang X. Intelligent freeform manufacturing of complex organs. Artif Organs 2012;36:951–61.
[159] Lee W, Debasitis JC, Lee VK, Lee J-H, Fischer K, Edminster K, et al. Multi- layered culture of human skin fibroblasts and
keratinocytes through three- dimensional
freeform
fabrication.
Biomaterials
2009;30:1587–95.
[160] Pereira RF, Barrias CC, Granja PL, Bartolo PJS. Advanced biofabrication strategies for
Nanomedicine 2013;8:603–21.
skin regeneration
and repair.