Top

Current Osteoporosis Reports

Published in:

01-08-2017 | Cancer-induced Musculoskeletal Diseases (M Reagan and E Keller, Section Editors)

Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments

Authors: Kristin A. Kwakwa, Joseph P. Vanderburgh, Scott A. Guelcher, Julie A. Sterling

Published in: Current Osteoporosis Reports | Issue 4/2017

Abstract

Purpose of Review

Bone is a structurally unique microenvironment that presents many challenges for the development of 3D models for studying bone physiology and diseases, including cancer. As researchers continue to investigate the interactions within the bone microenvironment, the development of 3D models of bone has become critical.

Recent Findings

3D models have been developed that replicate some properties of bone, but have not fully reproduced the complex structural and cellular composition of the bone microenvironment. This review will discuss 3D models including polyurethane, silk, and collagen scaffolds that have been developed to study tumor-induced bone disease. In addition, we discuss 3D printing techniques used to better replicate the structure of bone.

Summary

3D models that better replicate the bone microenvironment will help researchers better understand the dynamic interactions between tumors and the bone microenvironment, ultimately leading to better models for testing therapeutics and predicting patient outcomes.

Ma XH, Piao S, Wang D, Mcafee QW, Nathanson KL, Lum JJ, et al. Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clin Cancer Res. 2011;17:3478–89.PubMedPubMedCentral

Lee JM, Mhawech-Fauceglia P, Lee N, Parsanian LC, Lin YG, Gayther SA, et al. A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro. Lab Investig. 2013;93:528–42.PubMed

Imamura Y, Mukohara T, Shimono Y, Funakoshi Y, Chayahara N, Toyoda M, et al. Comparison of 2D- and 3D-culture models as drug-testing platforms in breast cancer. Oncol Rep. 2015;33:1837–43.PubMed

Vantangoli MM, Madnick SJ, Huse SM, Weston P, Boekelheide K. MCF-7 human breast cancer cells form differentiated microtissues in scaffold-free hydrogels. PLoS One. 2015;10:1–20.

Härmä V, Virtanen J, Mäkelä R, Happonen A, Mpindi JP, Knuuttila M, et al. A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses. PLoS One. 2010;5:e10431.PubMedPubMedCentral

Cichon MA, Gainullin VG, Zhang Y, Radisky DC. Growth of lung cancer cells in three-dimensional microenvironments reveals key features of tumor malignancy. Integr Biol. 2012;4:440–8.

Luca AC, Mersch S, Deenen R, Schmidt S, Messner I, Schäfer KL, et al. Impact of the 3D microenvironment on phenotype, gene expression, and EGFR inhibition of colorectal cancer cell lines. PLoS One. 2013;8:e59689.PubMedPubMedCentral

Sokol ES, Miller DH, Breggia A, Spencer KC, Arendt LM, Gupta PB. Growth of human breast tissues from patient cells in 3D hydrogel scaffolds. Breast Cancer Res. 2016;18:1–13.

Xu X, Gurski LA, Zhang C, Harrington DA, Farach-Carson MC, Jia X. Recreating the tumor microenvironment in a bilayer, hyaluronic acid hydrogel construct for the growth of prostate cancer spheroids. Biomaterials. 2012;33:9049–60.PubMedPubMedCentral

10.

Szot CS, Buchanan CF, Freeman JW, Rylander MN. 3D in vitro bioengineered tumors based on collagen I hydrogels. Biomaterials. 2011;32:7905–12.PubMedPubMedCentral

11.

Riching KM, Cox BL, Salick MR, Pehlke C, Riching AS, Ponik SM, et al. 3D collagen alignment limits protrusions to enhance breast cancer cell persistence. Biophys J. 2014;107:2546–58.PubMedPubMedCentral

12.

Kleinman HK, Martin GR. Matrigel: basement membrane matrix with biological activity. Semin Cancer Biol. 2005;15:378–86.PubMed

13.

Lovitt CJ, Shelper TB, Avery VM. Evaluation of chemotherapeutics in a three-dimensional breast cancer model. J Cancer Res Clin Oncol. 2015;141:951–9.PubMed

14.

Hughes CS, Postovit LM, Lajoie GA. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics. 2010;10:1886–90.PubMed

15.

Chung IM, Enemchukwu NO, Khaja SD, Murthy N, Mantalaris A, García AJ. Bioadhesive hydrogel microenvironments to modulate epithelial morphogenesis. Biomaterials. 2008;29:2637–45.PubMedPubMedCentral

16.

Gurski LA, Petrelli NJ, Jia X, Farach-Carson MC. 3D matrices for anti-cancer drug testing and development. Oncol Issues. 2010;25:20–5.

17.

Gill BJ, Gibbons DL, Roudsari LC, Saik JE, Rizvi ZH, Roybal JD, et al. A synthetic matrix with independently tunable biochemistry and mechanical properties to study epithelial morphogenesis and EMT in a lung adenocarcinoma model. Cancer Res. 2012;72:6013–23.PubMedPubMedCentral

18.

Del Bufalo F, Manzo T, Hoyos V, Yagyu S, Caruana I, Jacot J, et al. 3D modeling of human cancer: a PEG-fibrin hydrogel system to study the role of tumor microenvironment and recapitulate the in vivo effect of oncolytic adenovirus. Biomaterials. 2016;84:76–85.PubMed

19.

Pradhan S, Hassani I, Seeto WJ, Lipke EA. PEG-fibrinogen hydrogels for three-dimensional breast cancer cell culture. J Biomed Mater Res Part A. 2017;105:236–52.

20.

Feder-Mengus C, Ghosh S, Reschner A, Martin I, Spagnoli GC. New dimensions in tumor immunology: what does 3D culture reveal? Trends Mol Med. 2008;14:333–40.PubMed

21.

Zanoni M, Piccinini F, Arienti C, Zamagni A, Santi S, Polico R, et al. 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci Rep. 2016;6:19103.PubMedPubMedCentral

22.

Vinci M, Gowan S, Boxall F, Patterson L, Zimmermann M, Court W, et al. Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation. BMC Biol. 2012;10:1–20.

23.

Breslin S, O’Driscoll L. Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today. 2013;18:240–9.PubMed

24.

Yip D, Cho CH. A multicellular 3D heterospheroid model of liver tumor and stromal cells in collagen gel for anti-cancer drug testing. Biochem Biophys Res Commun. 2013;433:327–32.PubMed

25.

Tung Y-C, Hsiao AY, Allen SG, Torisawa Y, Ho M, Takayama S. High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. Analyst. 2011;136:473–8.PubMed

26.

Amann A, Zwierzina M, Gamerith G, Bitsche M, Huber JM, Vogel GF, et al. Development of an innovative 3D cell culture system to study tumour—stroma interactions in non-small cell lung cancer cells. PLoS One. 2014;9:e92511.PubMedPubMedCentral

27.

Raghavan S, Ward MR, Rowley KR, Wold RM, Takayama S, Buckanovich RJ, et al. Formation of stable small cell number three-dimensional ovarian cancer spheroids using hanging drop arrays for preclinical drug sensitivity assays. Gynecol Oncol. 2015;138:181–9.PubMedPubMedCentral

28.

Raghavan S, Mehta P, Horst EN, Ward MR, Rowley KR, Mehta G. Comparative analysis of tumor spheroid generation techniques for differential in vitro drug toxicity. Oncotarget. 2016;7:16948–61.PubMedPubMedCentral

29.

Aboulafia AJ, Levine AM, Schmidt D, Aboulafia D. Surgical therapy of bone metastases. Semin Oncol. 2007;34:206–14.PubMed

30.

Johnson RW, Schipani E, Giaccia AJ. HIF targets in bone remodeling and metastatic disease. Pharmacol Ther. 2015;150:169–77.PubMedPubMedCentral

31.

Guelcher SA, Sterling JA. Contribution of bone tissue modulus to breast cancer metastasis to bone. Cancer Microenviron. 2011;4:247–59.PubMedPubMedCentral

32.

Page JM, Merkel AR, Ruppender NS, Guo R, Dadwal UC, Cannonier SA, et al. Matrix rigidity regulates the transition of tumor cells to a bone-destructive phenotype through integrin β3 and TGF-β receptor type II. Biomaterials. 2015;64:33–44.PubMedPubMedCentral

33.

García-Alvarez R, Izquierdo-Barba I, Vallet-Regí M. 3D scaffold with effective multidrug sequential release against bacteria biofilm. Acta Biomater. 2016;49:113–26.PubMed

34.

Sundelacruz S, Li C, Choi YJ, Levin M, Kaplan DL. Bioelectric modulation of wound healing in a 3D invitro model of tissue-engineered bone. Biomaterials. 2013;34:6695–705.PubMedPubMedCentral

35.

Lee JH, Gu Y, Wang H, Lee WY. Microfluidic 3D bone tissue model for high-throughput evaluation of wound-healing and infection-preventing biomaterials. Biomaterials. 2012;33:999–1006.PubMed

36.

Chatterjee K, Lin-Gibson S, Wallace WE, Parekh SH, Lee YJ, Cicerone MT, et al. The effect of 3D hydrogel scaffold modulus on osteoblast differentiation and mineralization revealed by combinatorial screening. Biomaterials. 2010;31:5051–62.PubMedPubMedCentral

37.

Guo R, Lu S, Page JM, Merkel AR, Basu S, Sterling JA, et al. Fabrication of 3D scaffolds with precisely controlled substrate modulus and pore size by templated-fused deposition modeling to direct osteogenic differentiation. Adv Healthc Mater. 2015;4:1826–32.PubMedPubMedCentral

38.

Sun L, Parker ST, Syoji D, Wang X, Lewis JA, Kaplan DL. Direct-write assembly of 3D silk/hydroxyapatite scaffolds for bone co-cultures. Adv Healthc Mater. 2012;1:729–35.PubMedPubMedCentral

39.

Bidan CM, Kommareddy KP, Rumpler M, Kollmannsberger P, Fratzl P, Dunlop JWC. Geometry as a factor for tissue growth: towards shape optimization of tissue engineering scaffolds. Adv Healthc Mater. 2013;2:186–94.PubMed

40.

Gamsjager E, Bidan CM, Fischer FD, Fratzl P, Dunlop JWC. Modelling the role of surface stress on the kinetics of tissue growth in confined geometries. Acta Biomater. 2013;9:5531–43.PubMed

41.

Sterling JA, Guelcher SA. Bone structural components regulating sites of tumor metastasis. Curr Osteoporos Rep. 2011;9:89–95.PubMedPubMedCentral

42.

Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in 3D. Cell. 2007;130:601–10.PubMed

43.

Fischbach C, Chen R, Matsumoto T, Schmelzle T, Brugge JS, Polverini PJ, et al. Engineering tumors with 3D scaffolds. Nat Methods. 2007;4:855–60.PubMed

44.

Schuessler TK, Chan XY, Chen HJ, Ji K, Park KM, Roshan-Ghias A, et al. Biomimetic tissue-engineered systems for advancing cancer research: NCI strategic workshop report. Cancer Res. 2014;74:5359–63.PubMedPubMedCentral

45.

Temple JP, Hutton DL, Hung BP, Huri PY, Cook CA, Kondragunta R, et al. Engineering anatomically shaped vascularized bone grafts with hASCs and 3D-printed PCL scaffolds. J Biomed Mater Res Part A. 2014;102:4317–25.

46.

Williams JM, Adewunmi A, Schek RM, Flanagan CL, Krebsbach PH, Feinberg SE, et al. Bone tissue engineering using polycaprolactone scaffolds fabricated via selective laser sintering. Biomaterials. 2005;26:4817–27.PubMed

47.

Petrie Aronin CE, Cooper JA, Sefcik LS, Tholpady SS, Ogle RC, Botchwey EA. Osteogenic differentiation of dura mater stem cells cultured in vitro on three-dimensional porous scaffolds of poly(epsilon-caprolactone) fabricated via co-extrusion and gas foaming. Acta Biomater. 2008;4:1187–97.PubMed

48.

Guillaume O, Geven MA, Sprecher CM, Stadelmann VA, Grijpma DW, Tang TT, et al. Surface-enrichment with hydroxyapatite nanoparticles in stereolithography-fabricated composite polymer scaffolds promotes bone repair. Acta Biomater. 2017;54:386–98.PubMed

49.

Gay S, Arostegui S, Lemaitre J. Preparation and characterization of dense nanohydroxyapatite/PLLA composites. Mater Sci Eng C. 2009;29:172–7.

50.

Grinberg O, Binderman I, Bahar H, Zilberman M. Highly porous bioresorbable scaffolds with controlled release of bioactive agents for tissue-regeneration applications. Acta Biomater Acta Materialia Inc. 2010;6:1278–87.

51.

Horning JL, Sahoo SK, Vijayaraghavalu S, Dimitrijevic S, Vasir JK, Jain TK, et al. 3-D tumor model for in vitro evaluation of anticancer drugs. Mol Pharm. 2008;5:849–62.PubMed

52.

Zhang P, Wu H, Wu H, Lù Z, Deng C, Hong Z, et al. RGD-conjugated copolymer incorporated into composite of poly(lactide-co-glycotide) and poly(L-lactide)-grafted nanohydroxyapatite for bone tissue engineering. Biomacromolecules. 2011;12:2667–80.PubMed

53.

Guelcher SA. Biodegradable polyurethanes: synthesis and applications in regenerative medicine. Tissue Eng Part B Rev. 2008;14:3–17.PubMed

54.

Temenoff JS, Mikos AG. Injectable biodegradable materials for orthopedic tissue engineering. Biomaterials. 2000;21:2405–12.PubMed

55.

Kim K, Dean D, Mikos AG, Fisher JP. Effect of initial cell seeding density on early osteogenic signal expression of rat bone marrow stromal cells cultured on cross-linked poly(propylene fumarate) disks. Biomacromolecules. 2009;10:1810–7.PubMedPubMedCentral

56.

Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3:S131–9.PubMedPubMedCentral

57.

Chattopadhyay S, Raines RT. Collagen-based biomaterials for wound healing. Biopolymers. 2015;101:821–33.

58.

Reagan MR, Mishima Y, Glavey SV, Zhang Y, Manier S, Lu ZN, et al. Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model. Blood. 2014;124:3250–9.PubMedPubMedCentral

59.

Vepari C, Kaplan DL. Silk as a biomaterial. Prog Polym Sci. 2007;32:991–1007.PubMedPubMedCentral

60.

Kwon H, Kim HJ, Rice WL, Subramanian B, Park S, Georgakoudi I, et al. Development of an in vitro model to study the impact of BMP-2 on metastasis to bone. J Tissue Eng Regen Med. 2010;4:590–9.PubMedPubMedCentral

61.

Mastro AM, Vogler EA. A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. Cancer Res. 2009;69:4097–100.PubMed

62.

Thein-Han W, Xu HHK. Prevascularization of a gas-foaming macroporous calcium phosphate cement scaffold via coculture of human umbilical vein endothelial cells and osteoblasts. Tissue Eng Part A. 2013;19:1675–85.PubMedPubMedCentral

63.

Annabi N, Fathi A, Mithieux SM, Martens P, Weiss AS, Dehghani F. The effect of elastin on chondrocyte adhesion and proliferation on poly (epsilon-caprolactone)/elastin composites. Biomaterials Elsevier Ltd. 2011;32:1517–25.

64.

Akar B, Jiang B, Somo SI, Appel AA, Larson JC, Tichauer KM, et al. Biomaterials with persistent growth factor gradients in vivo accelerate vascularized tissue formation. Biomaterials. 2015;72:61–73.PubMed

65.

Zhang J, Zhou H, Yang K, Yuan Y, Liu C. RhBMP-2-loaded calcium silicate/calcium phosphate cement scaffold with hierarchically porous structure for enhanced bone tissue regeneration. Biomaterials. 2013;34:9381–92.PubMed

66.

Fereshteh Z, Fathi M, Bagri A, Boccaccini AR. Preparation and characterization of aligned porous PCL/zein scaffolds as drug delivery systems via improved unidirectional freeze-drying method. Mater Sci Eng C. 2016;68:613–22.

67.

Vanderburgh J, Sterling JA, Guelcher SA. 3D printing of tissue engineered constructs for in vitro modeling of disease progression and drug screening. Ann Biomed Eng. 2016;1–16.

68.

Hutmacher DW, Schantz T, Zein I, Ng KW, Teoh SH, Tan KC. Mechanical properties and cell cultural response of polycaprolactone scaffolds designed and fabricated via fused deposition modeling. J Biomed Mater Res. 2001;55:203–16.PubMed

69.

Guo R, Merkel AR, Sterling JA, Davidson JM, Guelcher SA. Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling. Biomaterials. 2015;73:85–95.PubMedPubMedCentral

70.

Lee S-J, Nowicki M, Harris B, Zhang LG. Fabrication of a highly aligned neural scaffold via a table top stereolithography 3D printing and electrospinning. Tissue Eng Part A. 2017;

71.

Li G, Cuidi L, Fangping C, Changsheng L. Fabrication and characterization of toughness-enhanced scaffolds comprising beta-TCP/POC using the freeform fabrication system with micro-droplet jetting. Biomed Mater. 2015;10:35009.

72.

Kundu J, Shim JH, Jang J, Kim SW, Cho DW. An additive manufacturing-based PCL-alginate-chondrocyte bioprinted scaffold for cartilage tissue engineering. J Tissue Eng Regen Med. 2015;9:1286–97.PubMed

73.

Kang HW, Lee SJ, Ko IK, Kengla C, Yoo JJ, Atala A. A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat Biotechnol. 2016;34:312–9.

74.

Bancroft GN, Sikavitsas VI, van den Dolder J, Sheffield TL, Ambrose CG, Jansen JA, et al. Fluid flow increases mineralized matrix deposition in 3D perfusion culture of marrow stromal osteoblasts in a dose-dependent manner. Proc Natl Acad Sci U S A. 2002;99:12600–5.PubMedPubMedCentral

75.

• Krishnan V, Vogler EA, Mastro AM. Three-dimensional in vitro model to study osteobiology and osteopathology. J Cell Biochem. 2015;116:2715–23. This study uses a 3D bioreactor tri-culture model to demonstrate that tumor cells migrate towards sites of active bone remodeling which results in further degradation of osteoid matrix. PubMed

76.

Talukdar S, Nguyen QT, Chen AC, Sah RL, Kundu SC. Effect of initial cell seeding density on 3D-engineered silk fibroin scaffolds for articular cartilage tissue engineering. Biomaterials. 2011;32:8927–37.PubMedPubMedCentral

77.

Talukdar S, Kundu SC. Engineered 3D silk-based metastasis models: interactions between human breast adenocarcinoma, mesenchymal stem cells and osteoblast-like cells. Adv Funct Mater. 2013;23:5249–60.

78.

Mastro AM, Gay CV, Welch DR, Donahue HJ, Jewell J, Mercer R, et al. Breast cancer cells induce osteoblast apoptosis: a possible contributor to bone degradation. J Cell Biochem. 2004;91:265–76.PubMed

79.

• Subia B, Dey T, Sharma S, Kundu SC. Target specific delivery of anticancer drug in silk fibroin based 3D distribution model of bone–breast cancer cells. ACS Appl Mater Interfaces. 2015;7:2269–79. This study reports that the viability, invasiveness, and angiogenic potential of cancer cells co-cultured with osteoblasts on silk scaffolds significantly decreases after nanoparticle-targeted delivery of doxorubicin; osteoblasts were mostly unaffected by treatment. PubMed

80.

• Lynch ME, Chiou AE, Lee MJ, Marcott SC, Polamraju PV, Lee Y, et al. Three-dimensional mechanical loading modulates the osteogenic response of mesenchymal stem cells to tumor-derived soluble signals. Tissue Eng Part A. 2016;22:1006–15. This paper emphasizes the important role that mechanical stress plays on osteogenic cells cultured on HA-containing scaffolds in the presence of tumor-conditioned media. PubMedPubMedCentral

81.

• Zhu W, Holmes B, Glazer RI, Zhang LG. 3D printed nanocomposite matrix for the study of breast cancer bone metastasis. Nanomedicine Nanotechnol Biol Med. 2016;12:69–79. This study utilizes a novel stereolithography-based 3D printer to fabricate nanohydroxyapatite scaffolds that promote tumor spheroid formation, proliferation, and migration; tumor cells also exhibit more chemoresistance on 3D scaffolds.

82.

Wang Y, Pivonka P, Buenzli PR, Smith DW, Dunstan CR. Computational modeling of interactions between multiple myeloma and the bone microenvironment. PLoS One. 2011;6:e27494.PubMedPubMedCentral

83.

Araujo A, Cook LM, Lynch CC, Basanta D. An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer. Cancer Res. 2014;14:2391–401.

Title: Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments
Authors: Kristin A. Kwakwa
Joseph P. Vanderburgh
Scott A. Guelcher
Julie A. Sterling
Publication date: 01-08-2017
Publisher: Springer US
Published in: Current Osteoporosis Reports / Issue 4/2017
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI: https://doi.org/10.1007/s11914-017-0385-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments

Abstract

Purpose of Review

Recent Findings

Summary

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 4/2017

Erratum to: Microcephalic Osteodysplastic Primordial Dwarfism, Type II: a Clinical Review

Osteocyte Mechanobiology

Recent Discoveries in Monogenic Disorders of Childhood Bone Fragility

Response to “Clinical Evaluation of Bone Strength and Fracture Risk”

In vivo Visualisation and Quantification of Bone Resorption and Bone Formation from Time-Lapse Imaging

Gut Microbiome and Bone: to Build, Destroy, or Both?