Skip to main content

Advertisement

SpringerLink
Log in

Pre-clinical Characterization of Tissue Engineering Constructs for Bone and Cartilage Regeneration

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

125I:

Iodine-125

2D:

Two-dimensional

3D:

Three-dimensional

3D-SPGR:

Three-dimensional spoiled gradient recalled echo imaging with fat suppression

AB:

Alcian blue

BLI:

Bioluminescent imaging

BMP(-2,-7):

Bone morphogenetic protein (-2,-7)

BSE:

Backscattered electron

CECT:

Contrast-enhanced computed tomography

DBM:

Demineralized bone matrix

dGEMRIC:

Delayed gadolinium enhanced magnetic resonance imaging of cartilage

ECM:

Extracellular matrix

EPIC-microCT:

Equilibrium partitioning of ionic contrast agent micro-computed tomography

FG:

Fast green

eGFP:

Enhanced green fluorescent protein

GAG:

Glycosaminoglycan

gagCEST:

Glycosaminoglycan-specific chemical exchange saturation transfer

GT:

Goldner’s trichrome

H&E:

Hematoxylin and eosin

HA:

Hydroxyapatite

hAMSC:

Human adipose tissue-derived mesenchymal stem cells

hBMSC:

Human bone marrow stromal cells

hMSC:

Human mesenchymal stem cells

ICRS:

International Cartilage Repair Society

IHC:

Immunohistochemistry

ISO:

International Organization for Standardization

IVUS:

Intravascular ultrasound

Luc:

Luciferase

microCT:

Micro-computed tomography

MB:

Methylene blue

MP:

Microparticle

MRI:

Magnetic resonance imaging

MSC:

Mesenchymal stem cell

MT:

Masson’s trichrome

NF-κB:

Necrotic factor-κB

OAS:

Oswestry arthroscopy score

OCT:

Optical coherence tomography

PAM:

Photoacoustic microscopy

ROI:

Region of interest

PCL:

Poly(ε-caprolactone)

PDGF:

Platelet-derived growth factor

PEG:

Poly(ethylene glycol)

PG:

Proteoglycan

PGA:

Poly(glycolic acid)

PIPAAm:

Poly(isopropylacrylamide)

PLA:

Poly(lactic acid)

PLGA:

Poly(dl-lactic-co-glycolic acid)

PLLA:

Poly(l-lactic acid)

PPF:

Poly(propylene fumarate)

PVDF:

Poly(vinylidene difluoride)

RGD:

Arginylglycylaspartic acid

rhBMP-2:

Human recombinant BMP-2

Saf O:

Safranin O

SEM:

Scanning electron microscopy

SNR:

Signal-to-noise ratio

SPECT:

Single photon emission computed tomography

SPIO:

Superparamagnetic iron oxide

TB:

Toluidine blue

TCP:

Tricalcium phosphate

TGF-β1:

Transforming growth factor-β1

TRITC:

Tetramethylrhodamine isothiocyanate

US:

Utrasound

uTE:

Ultra-short echo time

VG:

van Gieson

VK:

von Kossa

WK:

Working standard (ASTM)

References

  1. Abdulreda, M. H., G. Faleo, R. D. Molano, M. Lopez-Cabezas, J. Molina, Y. Tan, O. A. Echeverria, E. Zahr-Akrawi, R. Rodriguez-Diaz, P. K. Edlund, I. Leibiger, A. L. Bayer, V. Perez, C. Ricordi, A. Caicedo, A. Pileggi, and P. O. Berggren. High-resolution, noninvasive longitudinal live imaging of immune responses. Proc. Natl. Acad. Sci. USA 108:12863–12868, 2011.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Allen, A., Z. Gazit, S. Su, H. Stevens, and R. E. Guldberg. In vivo bioluminescent tracker of mesechymal stem cells within large hydrogel constructs. Tissue Eng. Part C. 20:1–11, 2014.

    CAS  Google Scholar 

  3. An, Y. H., and R. A. Draughn. Mechanical testing of bone and the bone-implant interface (1st ed.). Boca Raton, FL: CRC Press, p. 624, 1999.

    Google Scholar 

  4. Appel, A. A., M. A. Anastasio, J. C. Larson, and E. M. Brey. Imaging challenges in biomaterials and tissue engineering. Biomaterials. 34:6615–6630, 2013.

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Artzi, N., N. Oliva, C. Puron, S. Shitreet, S. Artzi, A. bon Ramos, A. Groothuis, G. Sahagian, and E. R. Edelman. In vivo and in vitro tracking of erosion in biodegradable materials using non-invasive fluorescence imaging. Nat Mater. 10:704–709, 2011.

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Aula, A. S., J. S. Jurvelin, and J. Toyras. Simultaneous computed tomography of articular cartilage and subchondral bone. Osteoarthr. Cartil. 17:1583–1588, 2009.

    CAS  PubMed  Google Scholar 

  7. Badea, C. T., M. Drangova, D. W. Holdsworth, and G. A. Johnson. In vivo small-animal imaging using micro-ct and digital subtraction angiography. Phys. Med. Biol. 53:R319–R350, 2008.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Badylak, S. F., J. E. Valentin, A. K. Ravindra, G. P. McCabe, and A. M. Stewart-Akers. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng. Part A. 14:1835–1842, 2008.

    CAS  PubMed  Google Scholar 

  9. Bae, W. C., J. R. Dwek, R. Znamirowski, S. M. Statum, J. C. Hermida, D. D. D’Lima, R. L. Sah, J. Du, and C. B. Chung. Ultrashort echo time mr imaging of osteochondral junction of the knee at 3 t: identification of anatomic structures contributing to signal intensity. Radiology. 254:837–845, 2010.

    PubMed Central  PubMed  Google Scholar 

  10. Bae, W. C., B. L. Schumacher, and R. L. Sah. Indentation probing of human articular cartilage: effect on chondrocyte viability. Osteoarthr. Cartil. 15:9–18, 2007.

    CAS  PubMed  Google Scholar 

  11. Bago, J. R., E. Aguilar, M. Alieva, C. Soler-Botija, O. F. Vila, S. Claros, J. A. Andrades, J. Becerra, N. Rubio, and J. Blanco. In vivo bioluminescence imaging of cell differentiation in biomaterials: a platform for scaffold development. Tissue Eng. Part A. 19:593–603, 2013.

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Bansal, P. N., N. S. Joshi, V. Entezari, M. W. Grinstaff, and B. D. Snyder. Contrast enhanced computed tomography can predict the glycosaminoglycan content and biomechanical properties of articular cartilage. Osteoarthr. Cartil. 18:184–191, 2010.

    CAS  PubMed  Google Scholar 

  13. Boerckel, J. D., Y. M. Kolambkar, K. M. Dupont, B. A. Uhrig, E. A. Phelps, H. Y. Stevens, A. J. Garcia, and R. E. Guldberg. Effects of protein dose and delivery system on bmp-mediated bone regeneration. Biomaterials. 32:5241–5251, 2011.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Bonasia, D., A. Marmotti, A. Massa, A. Ferro, D. Blonna, F. Castoldi, and R. Rossi. Intra-and inter-observer reliability of ten major histological scoring systems used for the evaluation of in vivo cartilage repair. Berlin: Springer, 2014.

    Google Scholar 

  15. Bouxsein, M. L., S. K. Boyd, B. A. Christiansen, R. E. Guldberg, K. J. Jepsen, and R. Muller. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J. Bone Miner. Res. 25:1468–1486, 2010.

    PubMed  Google Scholar 

  16. Boyd, S. K., P. Davison, R. Muller, and J. A. Gasser. Monitoring individual morphological changes over time in ovariectomized rats by in vivo micro-computed tomography. Bone. 39:854–862, 2006.

    PubMed  Google Scholar 

  17. Braun, H. J., J. L. Dragoo, B. A. Hargreaves, M. E. Levenston, and G. E. Gold. Application of advanced magnetic resonance imaging techniques in evaluation of the lower extremity. Radiol. Clin. North Am. 51:529–545, 2013.

    PubMed Central  PubMed  Google Scholar 

  18. Brommer, H., M. S. Laasanen, P. A. J. Brama, P. R. Van Weeren, H. J. Helminen, and J. S. Jurvelin. In situ and ex vivo evaluation of an arthroscopic indentation instrument to estimate the health status of articular cartilage in the equine metacarpophalangeal joint. Vet. Surg. 35:259–266, 2006.

    PubMed  Google Scholar 

  19. Brown, B. N., B. D. Ratner, S. B. Goodman, S. Amar, and S. F. Badylak. Macrophage polarization: an opportunity for improved outcomes in and regenerative medicine. Biomaterials. 33:3792–3802, 2012.

    PubMed Central  CAS  PubMed  Google Scholar 

  20. Brown, K. V., B. Li, T. Guda, D. S. Perrien, S. A. Guelcher, and J. C. Wenke. Improving bone formation in a rat femur segmental defect by controlling bone morphogenetic protein-2 release. Tissue Eng. Part A. 17:1735–1746, 2011.

    CAS  PubMed  Google Scholar 

  21. Cai, X., Y. Zhang, L. Li, S. W. Choi, M. R. MacEwan, J. J. Yao, C. Kim, Y. N. Xia, and L. H. V. Wang. Investigation of neovascularization in three-dimensional porous scaffolds in vivo by a combination of multiscale photoacoustic microscopy and optical coherence tomography. Tissue Eng. Part C Methods. 19:196–204, 2013.

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Cancedda, R., P. Giannoni, and M. Mastrogiacomo. A tissue engineering approach to bone repair in large animal models and in clinical practice. Biomaterials. 28:4240–4250, 2007.

    CAS  PubMed  Google Scholar 

  23. Changoor, A., N. Tran-Khanh, S. Methot, M. Garon, M. B. Hurtig, M. S. Shive, and M. D. Buschmann. A polarized light microscopy method for accurate and reliable grading of collagen organization in cartilage repair. Osteoarthr. Cartil. 19:126–135, 2011.

    CAS  PubMed  Google Scholar 

  24. Chavhan, G. B., P. S. Babyn, B. Thomas, M. M. Shroff, and E. M. Haacke. Principles, techniques, and applications of T2*-based mr imaging and its special applications. Radiographics. 29:1433–1449, 2009.

    PubMed Central  PubMed  Google Scholar 

  25. Chawla, K., T. J. Klein, B. L. Schumacher, K. D. Jadin, B. H. Shah, K. Nakagawa, V. W. Wong, A. C. Chen, K. Masuda, and R. L. Sah. Short-term retention of labeled chondrocyte subpopulations in stratified tissue-engineered cartilaginous constructs implanted in vivo in mini-pigs. Tissue Eng. 13:1525–1537, 2007.

    CAS  PubMed  Google Scholar 

  26. Chen, J., H. Chen, P. Li, H. Diao, S. Zhu, L. Dong, R. Wang, T. Guo, J. Zhao, and J. Zhang. Simultaneous regeneration of articular cartilage and subchondral bone in vivo using MSCs induced by a spatially controlled gene delivery system in bilayered integrated scaffolds. Biomaterials. 32:4793–4805, 2011.

    CAS  PubMed  Google Scholar 

  27. Chen, J. W., C. Y. Wang, S. H. Lu, J. Z. Wu, X. M. Guo, C. M. Duan, L. Z. Dong, Y. Song, J. C. Zhang, D. Y. Jing, L. B. Wu, J. D. Ding, and D. X. Li. In vivo chondrogenesis of adult bone-marrow-derived autologous mesenchymal stem cells. Cell Tissue Res. 319:429–438, 2005.

    PubMed  Google Scholar 

  28. Chen, Y., Y. T. Yan, X. M. Li, H. Li, Y. Yuan, X. Y. Gao, X. X. Wu, J. S. Zhong, B. M. Lin, Y. B. Fan, and B. Yu. Osteogenesis capability and degradation property evaluation of injectable biomaterials: comparison of computed tomography and ultrasound. J. Nanomater. 4:763937, 2013.

    Google Scholar 

  29. Coatney, R. W. Ultrasound imaging: principles and applications in rodent research. ILAR J. 42:233–247, 2001.

    CAS  PubMed  Google Scholar 

  30. Cowles, E. A., J. L. Kovar, E. T. Curtis, H. Xu, and S. F. Othman. Near-infrared optical imaging for monitoring the regeneration of osteogenic tissue-engineered constructs. Biores. Open. Access. 2:186–191, 2013.

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Cunha-Reis, C., A. J. El Haj, X. Yang, and Y. Yang. Fluorescent labeling of chitosan for use in non-invasive monitoring of degradation in tissue engineering. J. Tissue Eng. Regen. Med. 7:39–50, 2013.

    CAS  PubMed  Google Scholar 

  32. Da, H., S. J. Jia, G. L. Meng, J. H. Cheng, W. Zhou, Z. Xiong, Y. J. Mu, and J. Liu. The impact of compact layer in biphasic scaffold on osteochondral tissue engineering. PLoS One. 8:e54838, 2013.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. de Boer, J., C. van Blitterswijk, and C. Lowik. Bioluminescent imaging: emerging technology for non-invasive imaging of bone tissue engineering. Biomaterials. 27:1851–1858, 2006.

    PubMed  Google Scholar 

  34. Degano, I. R., M. Vilalta, J. R. Bago, A. M. Matthies, J. A. Hubbell, H. Dimitriou, P. Bianco, N. Rubio, and J. Blanco. Bioluminescence imaging of calvarial bone repair using bone marrow and adipose tissue-derived mesenchymal stem cells. Biomaterials. 29:427–437, 2008.

    CAS  PubMed  Google Scholar 

  35. Delgado, J. J., C. Evora, E. Sanchez, M. Baro, and A. Delgado. Validation of a method for non-invasive in vivo measurement of growth factor release from a local delivery system in bone. J. Control. Release. 114:223–229, 2006.

    CAS  PubMed  Google Scholar 

  36. Dempster, D. W., J. E. Compston, M. K. Drezner, F. H. Glorieux, J. A. Kanis, H. Malluche, P. J. Meunier, S. M. Ott, R. R. Recker, and A. M. Parfitt. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR histomorphometry nomenclature committee. J. Bone Miner. Res. 28:2–17, 2013.

    PubMed Central  PubMed  Google Scholar 

  37. Deng, M., L. S. Nair, S. P. Nukavarapu, S. G. Kumbar, T. Jiang, A. L. Weikel, N. R. Krogman, H. R. Allcock, and C. T. Laurencin. In situ porous structures: a unique polymer erosion mechanism in biodegradable dipeptide-based polyphosphazene and polyester blends producing matrices for regenerative engineering. Adv. Funct. Mater. 20:2743–2957, 2010.

    PubMed Central  PubMed  Google Scholar 

  38. Ding, C., Z. Qiao, W. Jiang, H. Li, J. Wei, G. Zhou, and K. Dai. Regeneration of a goat femoral head using a tissue-specific, biphasic scaffold fabricated with CAD/CAM technology. Biomaterials. 34:6706–6716, 2013.

    CAS  PubMed  Google Scholar 

  39. Dupont, K. M., K. Sharma, H. Y. Stevens, J. D. Boerckel, A. J. Garcia, and R. E. Guldberg. Human stem cell delivery for treatment of large segmental bone defects. Proc. Natl. Acad. Sci. USA. 107:3305–3310, 2010.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Ertl, H. H., L. E. Feinendegen, and H. J. Heiniger. Iodine-125, a tracer in cell biology: physical properties and biological aspects. Phys. Med. Biol. 15:447–456, 1970.

    CAS  PubMed  Google Scholar 

  41. Farrell, E., P. Wielopolski, P. Pavljasevic, S. van Tiel, H. Jahr, J. Verhaar, H. Weinans, G. Krestin, F. J. O’Brien, G. van Osch, and M. Bernsen. Effects of iron oxide incorporation for long term cell tracking on MSC differentiation in vitro and in vivo. Biochem. Biophys. Res. Commun. 369:1076–1081, 2008.

    CAS  PubMed  Google Scholar 

  42. Ferland, C. E., S. Laverty, F. Beaudry, and P. Vachon. Gait analysis and pain response of two rodent models of osteoarthritis. Pharmacol. Biochem. Behav. 97:603–610, 2011.

    CAS  PubMed  Google Scholar 

  43. Ferreira, L., J. M. Karp, L. Nobre, and R. Langer. New opportunities: the use of nanotechnologies to manipulate and track stem cells. Cell Stem Cell. 3:136–146, 2008.

    CAS  PubMed  Google Scholar 

  44. Formica, D., and S. Silvestri. Biological effects of exposure to magnetic resonance imaging: an overview. Biomed. Eng. 3:11, 2004.

    Google Scholar 

  45. Foster, F. S., C. J. Pavlin, K. A. Harasiewicz, D. A. Christopher, and D. H. Turnbull. Advances in ultrasound biomicroscopy. Ultrasound Med. Biol. 26:1–27, 2000.

    CAS  PubMed  Google Scholar 

  46. Garcia-Seco, E., D. A. Wilson, J. L. Cook, K. Kuroki, J. M. Kreeger, and K. G. Keegan. Measurement of articular cartilage stiffness of the femoropatellar, tarsocrural, and metatarsophalangeal joints in horses and comparison with biochemical data. Vet. Surg. 34:571–578, 2005.

    PubMed  Google Scholar 

  47. Gauthier, O., R. Muller, D. von Stechow, B. Lamy, P. Weiss, J. M. Bouler, E. Aguado, and G. Daculsi. In vivo bone regeneration with injectable calcium phosphate biomaterial: a three-dimensional micro-computed tomographic, biomechanical and SEM study. Biomaterials. 26:5444–5453, 2005.

    CAS  PubMed  Google Scholar 

  48. Gerstenfeld, L. C., T. J. Wronski, J. O. Hollinger, and T. A. Einhorn. Application of histomorphometric methods to the study of bone repair. J. Bone Miner. Res. 20:1715–1722, 2005.

    PubMed  Google Scholar 

  49. Gildehaus, F. J., F. Haasters, I. Drosse, E. Wagner, C. Zach, W. Mutschler, P. Cumming, P. Bartenstein, and M. Schieker. Impact of indium-111 oxine labelling on viability of human mesenchymal stem cells in vitro, and 3d cell-tracking using SPECT/CT in vivo. Mol. Imag. Biol. 13:1204–1214, 2011.

    Google Scholar 

  50. Goebel, J. C., A. Pinzano, D. Grenier, A. L. Perrier, C. Henrionnet, L. Galois, P. Gillet, and O. Beuf. New trends in MRI of cartilage: advances and limitations in small animal studies. Biomed. Mater. Eng. 20:189–194, 2010.

    PubMed  Google Scholar 

  51. Gurcan, M., L. Boucheron, A. Can, A. Madabhushi, N. Rajpoot, and B. Yener. Histopathological image analysis: a review. IEEE Rev. Biomed. Eng. 2:147–171, 2009.

    PubMed Central  PubMed  Google Scholar 

  52. Hattori, K., T. Kumai, Y. Takakura, Y. Tanaka, and K. Ikeuchi. Ultrasound evaluation of cartilage damage in osteochondral lesions of the talar dome and correlation with clinical etiology: a preliminary report. Foot Ankle Int. 28:208–213, 2007.

    PubMed  Google Scholar 

  53. Hattori, K., Y. Takakura, H. Ohgushi, T. Habata, K. Uematsu, and K. Ikeuchi. Novel ultrasonic evaluation of tissue-engineered cartilage for large osteochondral defects–non-invasive judgment of tissue-engineered cartilage. J. Orthop. Res. 23:1179–1183, 2005.

    PubMed  Google Scholar 

  54. Haupert, S., S. Guerard, F. Peyrin, D. Mitton, and P. Laugier. Non destructive characterization of cortical bone micro-damage by nonlinear resonant ultrasound spectroscopy. PLoS One. 9:e83599, 2014.

    PubMed Central  PubMed  Google Scholar 

  55. Heymer, A., D. Haddad, M. Weber, U. Gbureck, P. M. Jakob, J. Eulert, and U. Noth. Iron oxide labelling of human mesenchymal stem cells in collagen hydrogels for articular cartilage repair. Biomaterials. 29:1473–1483, 2008.

    CAS  PubMed  Google Scholar 

  56. Ho, T. Y., Y. S. Chen, and C. Y. Hsiang. Noninvasive nuclear factor-kappa B bioluminescence imaging for the assessment of host-biomaterial interaction in transgenic mice. Biomaterials. 28:4370–4377, 2007.

    CAS  PubMed  Google Scholar 

  57. Hoemann, C., R. Kandel, S. Roberts, D. B. F. Saris, L. Creemers, P. Mainil-Varlet, S. Methot, A. P. Hollander, and M. D. Buschmann. International cartilage repair society (ICRS) recommended guidelines for histological endpoints for cartilage repair studies in animal models and clinical trials. Cartilage. 2:153–172, 2011.

    CAS  Google Scholar 

  58. Holland, T. A., Y. Tabata, and A. G. Mikos. Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering. J. Control. Release. 101:111–125, 2005.

    CAS  PubMed  Google Scholar 

  59. Horner, E. A., J. Kirkham, D. Wood, S. Curran, M. Smith, B. Thomson, and X. B. Yang. Long bone defect models for tissue engineering applications: criteria for choice. Tissue Eng. Part B Rev. 16:263–271, 2010.

    PubMed  Google Scholar 

  60. Huang, Y., V. Enzmann, and S. T. Ildstad. Stem cell-based therapeutic applications in retinal degenerative diseases. Stem Cell Rev. 7:434–445, 2011.

    PubMed Central  PubMed  Google Scholar 

  61. Hunziker, E. B. Biologic repair of articular cartilage. Defect models in experimental animals and matrix requirements. Clin. Orthop. Relat. Res. 367:S135–S146, 1999.

    PubMed  Google Scholar 

  62. Hunziker, E. B. Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthr. Cartil. 10:432–463, 2002.

    CAS  PubMed  Google Scholar 

  63. Hurtig, M. B., M. D. Buschmann, L. A. Fortier, C. D. Hoemann, E. B. Hunziker, J. S. Jurvelin, P. Mainil-Varlet, C. W. McIlwraith, R. L. Sah, and R. A. Whiteside. Preclinical studies for cartilage repair: recommendations from the international cartilage repair society. Cartilage. 2:137–152, 2011.

    Google Scholar 

  64. Jing, X. H., L. Yang, X. J. Duan, B. Xie, W. Chen, Z. Li, and H. B. Tan. In vivo MR imaging tracking of magnetic iron oxide nanoparticle labeled, engineered, autologous bone marrow mesenchymal stem cells following intra-articular injection. Joint Bone Spine. 75:432–438, 2008.

    PubMed  Google Scholar 

  65. Jones, A. C., B. Milthorpe, H. Averdunk, A. Limaye, T. J. Senden, A. Sakellariou, A. P. Sheppard, R. M. Sok, M. A. Knackstedt, A. Brandwood, D. Rohner, and D. W. Hutmacher. Analysis of 3d bone ingrowth into polymer scaffolds via micro-computed tomography imaging. Biomaterials. 25:4947–4954, 2004.

    CAS  PubMed  Google Scholar 

  66. Julkunen, P., R. K. Korhonen, W. Herzog, and J. S. Jurvelin. Uncertainties in indentation testing of articular cartilage: a fibril-reinforced poroviscoelastic study. Med. Eng. Phys. 30:506–515, 2008.

    PubMed  Google Scholar 

  67. Kaleva, E., S. Saarakkala, J. S. Jurvelin, T. Viren, and J. Toyras. Effects of ultrasound beam angle and surface roughness on the quantitative ultrasound parameters of articular cartilage. Ultrasound Med. Biol. 35:1344–1351, 2009.

    CAS  PubMed  Google Scholar 

  68. Kempen, D. H., L. Lu, K. L. Classic, T. E. Hefferan, L. B. Creemers, A. Maran, W. J. Dhert, and M. J. Yaszemski. Non-invasive screening method for simultaneous evaluation of in vivo growth factor release profiles from multiple ectopic bone tissue engineering implants. J. Control. Release. 130:15–21, 2008.

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Kempen, D. H., M. J. Yaszemski, A. Heijink, T. E. Hefferan, L. B. Creemers, J. Britson, A. Maran, K. L. Classic, W. J. Dhert, and L. Lu. Non-invasive monitoring of BMP-2 retention and bone formation in composites for bone tissue engineering using SPECT/CT and scintillation probes. J. Control. Release. 134:169–176, 2009.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Kim, K., C. G. Jeong, and S. J. Hollister. Non-invasive monitoring of tissue scaffold degradation using ultrasound elasticity imaging. Acta Biomater. 4:783–790, 2008.

    PubMed Central  PubMed  Google Scholar 

  71. Kim, K., J. Lam, S. Lu, P. P. Spicer, A. Lueckgen, Y. Tabata, M. E. Wong, J. A. Jansen, A. G. Mikos, and F. K. Kasper. Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model. J. Control. Release. 168:166–178, 2013.

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Kim, S. H., J. H. Lee, H. Hyun, Y. Ashitate, G. Park, K. Robichaud, E. Lunsford, S. J. Lee, G. Khang, and H. S. Choi. Near-infrared fluorescence imaging for noninvasive trafficking of scaffold degradation. Sci. Rep. 3:1198, 2013.

    PubMed Central  PubMed  Google Scholar 

  73. Kiviranta, P., E. Lammentausta, J. Toyras, I. Kiviranta, and J. S. Jurvelin. Indentation diagnostics of cartilage degeneration. Osteoarthr. Cartil. 16:796–804, 2008.

    CAS  PubMed  Google Scholar 

  74. Kretlow, J. D., P. P. Spicer, J. A. Jansen, C. A. Vacanti, F. K. Kasper, and A. G. Mikos. Uncultured marrow mononuclear cells delivered within fibrin glue hydrogels to porous scaffolds enhance bone regeneration within critical-sized rat cranial defects. Tissue Eng. Part A. 16:3555–3568, 2010.

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Lalande, C., S. Miraux, S. M. Derkaoui, S. Mornet, R. Bareille, J. C. Fricain, J. M. Franconi, C. Le Visage, D. Letourneur, J. Amedee, and A. K. Bouzier-Sore. Magnetic resonance imaging tracking of human adipose derived stromal cells within three-dimensional scaffolds for bone tissue engineering. Eur. Cell Mater. 21:341–354, 2011.

    CAS  PubMed  Google Scholar 

  76. Lau, S. F., C. F. Wolschrijn, M. Siebelt, J. C. Vernooij, G. Voorhout, and H. A. Hazewinkel. Assessment of articular cartilage and subchondral bone using epic-microCT in labrador retrievers with incipient medial coronoid disease. Vet. J. 198:116–121, 2013.

    CAS  PubMed  Google Scholar 

  77. Leblond, F., S. C. Davis, P. A. Valdes, and B. W. Pogue. Pre-clinical whole-body fluorescence imaging: review of instruments, methods and applications. J. Photochem. Photobiol. B. 98:77–94, 2010.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Lee, J. M., B. S. Kim, H. Lee, and G. I. Im. In vivo tracking of mesechymal stem cells using fluorescent nanoparticles in an osteochondral repair model. Mol Ther. 20:1434–1442, 2012.

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Logeart-Avramoglou, D., K. Oudina, M. Bourguignon, L. Delpierre, M. A. Nicola, M. Bensidhoum, E. Arnaud, and H. Petite. In vitro and in vivo bioluminescent quantification of viable stem cells in engineered constructs. Tissue Eng. Part C Methods. 16:447–458, 2010.

    CAS  PubMed  Google Scholar 

  80. Lu, M. H., Y. P. Zheng, H. B. Lu, Q. H. Huang, and L. Qin. Evaluation of bone-tendon junction healing using water jet ultrasound indentation method. Ultrasound Med. Biol. 35:1783–1793, 2009.

    PubMed  Google Scholar 

  81. Lu, X. L., D. D. Sun, X. E. Guo, F. H. Chen, W. M. Lai, and V. C. Mow. Indentation determined mechanoelectrochemical properties and fixed charge density of articular cartilage. Ann. Biomed. Eng. 32:370–379, 2004.

    PubMed  Google Scholar 

  82. Mainil-Varlet, P., B. Van Damme, D. Nesic, G. Knutsen, R. Kandel, and S. Roberts. A new histology scoring system for the assessment of the quality of human cartilage repair: ICRS II. Am. J. Sports Med. 38:880–890, 2010.

    PubMed  Google Scholar 

  83. Malluche, H. H., D. Sherman, W. Meyer, and S. G. Massry. A new semiautomatic method for quantitative static and dynamic bone-histology. Calcif. Tissue Int. 34:439–448, 1982.

    CAS  PubMed  Google Scholar 

  84. Mayr, H. O., J. Klehm, S. Schwan, R. Hube, N. P. Sudkamp, P. Niemeyer, G. Salzmann, R. von Eisenhardt-Rothe, A. Heilmann, M. Bohner, and A. Bernstein. Microporous calcium phosphate ceramics as tissue engineering scaffolds for the repair of osteochondral defects: biomechanical results. Acta Biomater. 9:4845–4855, 2013.

    CAS  PubMed  Google Scholar 

  85. Muschler, G. F., V. P. Raut, T. E. Patterson, J. C. Wenke, and J. O. Hollinger. The design and use of animal models for translational research in bone tissue engineering and regenerative medicine. Tissue Eng. Part B Rev. 16:123–145, 2010.

    PubMed  Google Scholar 

  86. Na, H. B., I. C. Song, and T. Hyeon. Inorganic nanoparticles for MRI contrast agents. Adv. Mater. 21:2133–2148, 2009.

    CAS  Google Scholar 

  87. Nagase, H., S. Kumakura, and K. Shimada. Establishment of a novel objective and quantitative method to assess pain-related behavior in monosodium iodoacetate-induced osteoarthritis in rat knee. J. Pharmacol. Toxicol. Methods. 65:29–36, 2012.

    CAS  PubMed  Google Scholar 

  88. O’Driscoll, S. W., R. G. Marx, D. E. Beaton, Y. Miura, S. H. Gallay, and J. S. Fitzsimmons. Validation of a simple histological-histochemical cartilage scoring system. Tissue Eng. 7:313–320, 2001.

    PubMed  Google Scholar 

  89. Oei, E. H., J. van Tiel, W. H. Robinson, and G. E. Gold. Quantitative radiologic imaging techniques for articular cartilage composition: toward early diagnosis and development of disease-modifying therapeutics for osteoarthritis. Arthritis Care Res. (Hoboken). 66:1129–1141, 2014.

    PubMed Central  PubMed  Google Scholar 

  90. Olivo, C., J. Alblas, V. Verweij, A. J. Van Zonneveld, W. J. A. Dhert, and A. C. M. Martens. In vivo bioluminescence imaging study to monitor ectopic bone formation by luciferase gene marked mesenchymal stem cells. J. Orthop. Res. 26:901–909, 2008.

    CAS  PubMed  Google Scholar 

  91. Orth, P., D. Zurakowski, D. Wincheringer, and H. Madry. Reliability, reproducibility, and validation of five major histological scoring systems for experimental articular cartilage repair in the rabbit model. Tissue Eng. Part C Methods. 18:329–339, 2012.

    CAS  PubMed  Google Scholar 

  92. Owens, E. A., H. Hyun, S. H. Kim, J. H. Lee, G. Park, Y. Ashitate, J. Choi, G. H. Hong, S. Alyabyev, S. J. Lee, G. Khang, M. Henary, and H. S. Choi. Highly charged cyanine fluorophores for trafficking scaffold degradation. Biomed. Mater. 8:014109, 2013.

    PubMed Central  PubMed  Google Scholar 

  93. Palmer, A. W., R. E. Guldberg, and M. E. Levenston. Analysis of cartilage matrix fixed charge density and three-dimensional morphology via contrast-enhanced microcomputed tomography. Proc. Natl. Acad. Sci. USA. 103:19255–19260, 2006.

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Parfitt, A. M., M. K. Drezner, F. H. Glorieux, J. A. Kanis, H. Malluche, P. J. Meunier, S. M. Ott, and R. R. Recker. Bone histomorphometry: standardization of nomenclature, symbols, and units. J. Bone Miner. Res. 2:595–610, 1987.

    CAS  PubMed  Google Scholar 

  95. Park, H., J. S. Temenoff, T. A. Holland, Y. Tabata, and A. G. Mikos. Delivery of TGF-beta 1 and chondrocytes via injectable, biodegradable hydrogels for cartilage tissue engineering applications. Biomaterials. 26:7095–7103, 2005.

    CAS  PubMed  Google Scholar 

  96. Pennisi, P., S. S. Signorelli, S. Riccobene, G. Celotta, L. Di Pino, T. La Malfa, and C. E. Fiore. Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels. Osteoporos. Int. 15:389–395, 2004.

    CAS  PubMed  Google Scholar 

  97. Pineda, S., A. Pollack, S. Stevenson, V. Goldberg, and A. Caplan. A semiquantitative scale for histologic grading of articular-cartilage repair. Acta Anat. (Basel) 143:335–340, 1992.

    CAS  Google Scholar 

  98. Potter, H. G., J. M. Linklater, A. A. Allen, J. A. Hannafin, and S. B. Haas. Magnetic resonance imaging of articular cartilage in the knee: an evaluation with use of fast-spin-echo imaging. J. Bone Joint Surg. Am. 80A:1276–1284, 1998.

    Google Scholar 

  99. Preville, A. M., P. Lavigne, M. D. Buschmann, J. Hardin, Q. Han, L. Djerroud, and P. Savard. Electroarthrography: a novel method to assess articular cartilage and diagnose osteoarthritis by non-invasive measurement of load-induced electrical potentials at the surface of the knee. Osteoarthr. Cartil. 21:1731–1737, 2013.

    PubMed  Google Scholar 

  100. Progatzky, F., M. J. Dallman, and C. Lo Celso. From seeing to believing: labelling strategies for in vivo cell-tracking experiments. Interface Focus. 3:20130001, 2013.

    PubMed Central  PubMed  Google Scholar 

  101. Quenneville, E., J. S. Binette, M. Garon, A. Legare, M. Meunier, and M. D. Buschmann. Fabrication and characterization of nonplanar microelectrode array circuits for use in arthroscopic diagnosis of cartilage diseases. IEEE Trans. Biomed. Eng. 51:2164–2173, 2004.

    PubMed  Google Scholar 

  102. Quintavalla, J., S. Uziel-Fusi, J. Y. Yin, E. Boehnlein, G. Pastor, V. Blancuzzi, H. N. Singh, K. H. Kraus, E. O’Byrne, and T. C. Pellas. Fluorescently labeled mesenchymal stem cells (MSCS) maintain multilineage potential and can be detected following implantation into articular cartilage defects. Biomaterials. 23:109–119, 2002.

    CAS  PubMed  Google Scholar 

  103. Ramaswamy, S., J. B. Greco, M. C. Uluer, Z. J. Zhang, Z. L. Zhang, K. W. Fishbein, and R. G. Spencer. Magnetic resonance imaging of chondrocytes labeled with superparamagnetic iron oxide nanoparticles in tissue-engineered cartilage. Tissue Eng. Part A. 15:3899–3910, 2009.

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Reinholz, G. G., L. Lu, D. B. Saris, M. J. Yaszemski, and S. W. O’Driscoll. Animal models for cartilage reconstruction. Biomaterials. 25:1511–1521, 2004.

    CAS  PubMed  Google Scholar 

  105. Rutgers, M., M. J. van Pelt, W. J. Dhert, L. B. Creemers, and D. B. Saris. Evaluation of histological scoring systems for tissue-engineered, repaired and osteoarthritic cartilage. Osteoarthr. Cartil. 18:12–23, 2010.

    CAS  PubMed  Google Scholar 

  106. Saarakkala, S., M. S. Laasanen, J. S. Jurvelin, and J. Toyras. Quantitative ultrasound imaging detects degenerative changes in articular cartilage surface and subchondral bone. Phys. Med. Biol. 51:5333–5346, 2006.

    PubMed  Google Scholar 

  107. Saldanha, K. J., R. P. Doan, K. M. Ainslie, T. A. Desai, and S. Majumdar. Micrometer-sized iron oxide particle labeling of mesenchymal stem cells for magnetic resonance imaging-based monitoring of cartilage tissue engineering. Magn. Reson. Imaging. 29:40–49, 2011.

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Santo, V. E., M. E. Gomes, J. F. Mano, and R. L. Reis. Controlled release strategies for bone, cartilage, and osteochondral engineering-part II: challenges on the evolution from single to multiple bioactive factor delivery. Tissue Eng. Part B Rev. 19:327–352, 2013.

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Schek, R. M., J. M. Taboas, S. J. Segvich, S. J. Hollister, and P. H. Krebsbach. Engineered osteochondral grafts using biphasic composite solid free-form fabricated scaffolds. Tissue Eng. 10:1376–1385, 2004.

    CAS  PubMed  Google Scholar 

  110. Schenck, J. F. The role of magnetic susceptibility in magnetic resonance imaging: MRI magnetic compatibility of the first and second kinds. Med. Phys. 23:815–850, 1996.

    CAS  PubMed  Google Scholar 

  111. Shi, L., S. P. Liu, D. F. Wang, H. L. Wong, W. H. Huang, Y. X. J. Wang, J. F. Griffith, P. C. Leung, and A. T. Ahuja. Computerized quantification of bone tissue and marrow in stained microscopic images. Cytometry Part A. 81A:916–921, 2012.

    Google Scholar 

  112. Stock, S. R. Recent advances in X-ray microtomography applied to materials. Int. Mater. Rev. 53:129–181, 2008.

    CAS  Google Scholar 

  113. Takaku, Y., K. Murai, T. Ukai, S. Ito, M. Kokubo, M. Satoh, E. Kobayashi, M. Yamato, T. Okano, M. Takeuchi, J. Mochida, and M. Sato. In vivo cell tracking by bioluminescence imaging after transplantation of bioengineered cell sheets to the knee joint. Biomaterials. 35:2199–2206, 2014.

    CAS  PubMed  Google Scholar 

  114. Tatebe, M., R. Nakamura, H. Kagami, K. Okada, and M. Ueda. Differentiation of transplanted mesenchymal stem cells in a large osteochondral defect in rabbit. Cytotherapy. 7:520–530, 2005.

    CAS  PubMed  Google Scholar 

  115. Toth, F., M. J. Nissi, J. Zhang, M. Benson, S. Schmitter, J. M. Ellermann, and C. S. Carlson. Histological confirmation and biological significance of cartilage canals demonstrated using high field MRI in swine at predilection sites of osteochondrosis. J. Orthop. Res. 31:2006–2012, 2013.

    PubMed Central  PubMed  Google Scholar 

  116. van den Borne, M. P., N. J. Raijmakers, J. Vanlauwe, J. Victor, S. N. de Jong, J. Bellemans, and D. B. Saris. International cartilage repair society (ICRS) and oswestry macroscopic cartilage evaluation scores validated for use in autologous chondrocyte implantation (ACI) and microfracture. Osteoarthr. Cartil. 15:1397–1402, 2007.

    PubMed  Google Scholar 

  117. van Lenthe, G. H., H. Hagenmuller, M. Bohner, S. J. Hollister, L. Meinel, and R. Muller. Nondestructive micro-computed tomography for biological imaging and quantification of scaffold-bone interaction in vivo. Biomaterials. 28:2479–2490, 2007.

    PubMed  Google Scholar 

  118. van Tiel, J., M. Siebelt, J. H. Waarsing, T. M. Piscaer, M. van Straten, R. Booij, M. L. Dijkshoorn, G. J. Kleinrensink, J. A. Verhaar, G. P. Krestin, H. Weinans, and E. H. Oei. CT arthrography of the human knee to measure cartilage quality with low radiation dose. Osteoarthr. Cartil. 20:678–685, 2012.

    PubMed  Google Scholar 

  119. Vilalta, M., C. Jorgensen, I. R. Degano, Y. Chernajovsky, D. Gould, D. Noel, J. A. Andrades, J. Becerra, N. Rubio, and J. Blanco. Dual luciferase labelling for non-invasive bioluminescence imaging of mesenchymal stromal cell chondrogenic differentiation in demineralized bone matrix scaffolds. Biomaterials. 30:4986–4995, 2009.

    CAS  PubMed  Google Scholar 

  120. Viren, T., S. Saarakkala, V. Tiitu, J. Puhakka, I. Kiviranta, J. S. Jurvelin, and J. Toyras. Ultrasound evaluation of mechanical injury of bovine knee articular cartilage under arthroscopic control. IEEE Trans. Ultrason. Ferroelectr. Freq. Control. 58:148–155, 2011.

    PubMed  Google Scholar 

  121. Vo, T. N., F. K. Kasper, and A. G. Mikos. Strategies for controlled delivery of growth factors and cells for bone regeneration. Adv. Drug Deliv. Rev. 64:1292–1309, 2012.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Vo, T. N., J. E. Trachtenberg, and A. G. Mikos. In vitro techniques for biomaterial evaluation in bone and cartilage tissue engineering. Regen. Med. J. Japanese Soc. Regen. Med. 13:125–149, 2014.

    Google Scholar 

  123. Waarsing, J. H., J. S. Day, and H. Weinans. An improved segmentation method for in vivo microct imaging. J. Bone Miner. Res. 19:1640–1650, 2004.

    PubMed  Google Scholar 

  124. Wakefield, R. J., P. V. Balint, M. Szkudlarek, E. Filippucci, M. Backhaus, M. A. D’Agostino, E. N. Sanchez, A. Iagnocco, W. A. Schmidt, G. Bruyn, D. Kane, P. J. O’Connor, B. Manger, F. Joshua, J. Koski, W. Grassi, M. N. D. Lassere, N. Swen, F. Kainberger, A. Klauser, M. Ostergaard, A. K. Brown, K. P. Machold, and P. G. Conaghan. Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J. Rheumatol. 32:2485–2487, 2005.

    PubMed  Google Scholar 

  125. Walker, J. M., A. M. Myers, M. D. Schluchter, V. M. Goldberg, A. I. Caplan, J. A. Berilla, J. M. Mansour, and J. F. Welter. Nondestructive evaluation of hydrogel mechanical properties using ultrasound. Ann. Biomed. Eng. 39:2521–2530, 2011.

    PubMed Central  PubMed  Google Scholar 

  126. Wang, S. Z., Y. P. Huang, S. Saarakkala, and Y. P. Zheng. Quantitative assessment of articular cartilage with morphologic, acoustic and mechanical properties obtained using high-frequency ultrasound. Ultrasound Med. Biol. 36:512–527, 2010.

    PubMed  Google Scholar 

  127. Wang, Y., Y. P. Huang, A. Liu, W. Wan, and Y. P. Zheng. An ultrasound biomicroscopic and water jet ultrasound indentation method for detecting the degenerative changes of articular cartilage in a rabbit model of progressive osteoarthritis. Ultrasound Med. Biol. 40:1296–1306, 2014.

    PubMed  Google Scholar 

  128. Weiss, P., L. Obadia, D. Magne, X. Bourges, C. Rau, T. Weitkamp, I. Khairoun, J. M. Bouler, D. Chappard, O. Gauthier, and G. Daculsi. Synchrotron X-ray microtomography (on a micron scale) provides three-dimensional imaging representation of bone ingrowth in calcium phosphate biomaterials. Biomaterials. 24:4591–4601, 2003.

    CAS  PubMed  Google Scholar 

  129. Wolfs, E., T. Struys, T. Notelaers, S. J. Roberts, A. Sohni, G. Bormans, K. Van Laere, F. P. Luyten, O. Gheysens, I. Lambrichts, C. M. Verfaillie, and C. M. Deroose. F-18-FDG labeling of mesenchymal stem cells and multipotent adult progenitor cells for pet imaging: effects on ultrastructure and differentiation capacity. J. Nucl. Med. 54:447–454, 2013.

    CAS  PubMed  Google Scholar 

  130. Xie, L., A. S. Lin, M. E. Levenston, and R. E. Guldberg. Quantitative assessment of articular cartilage morphology via epic-microct. Osteoarthr. Cartil. 17:313–320, 2009.

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Yang, Q., J. Peng, Q. Guo, J. Huang, L. Zhang, J. Yao, F. Yang, S. Wang, W. Xu, A. Wang, and S. Lu. A cartilage ECM-derived 3-D porous acellular matrix scaffold for in vivo cartilage tissue engineering with PKH26-labeled chondrogenic bone marrow-derived mesenchymal stem cells. Biomaterials. 29:2378–2387, 2008.

    CAS  PubMed  Google Scholar 

  132. Yoshioka, T., H. Mishima, Z. Kaul, Y. Ohyabu, S. Sakai, N. Ochiai, S. C. Kaul, R. Wadhwa, and T. Uemura. Fate of bone marrow mesenchymal stem cells following the allogeneic transplantation of cartilaginous aggregates into osteochondral defects of rabbits. J. Tissue Eng. Regen. Med. 5:437–443, 2011.

    CAS  PubMed  Google Scholar 

  133. Youn, J. I., T. Akkin, and T. E. Milner. Electrokinetic measurement of cartilage using differential phase optical coherence tomography. Physiol. Meas. 25:85–95, 2004.

    PubMed  Google Scholar 

  134. Zhang, Y. S., X. Cai, J. Yao, W. Xing, L. V. Wang, and Y. Xia. Non-invasive and in situ characterization of the degradation of biomaterial scaffolds by volumetric photoacoustic microscopy. Angew. Chem. Int. Ed. Engl. 53:184–188, 2014.

    PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge support by the National Institutes of Health (R01 AR048756) and the Armed Forces Institute of Regenerative Medicine II (W81XWH-14-2-0004) for work in the areas of bone and cartilage tissue engineering. J.E.T. acknowledges funding from the National Science Foundation Graduate Research Fellowship Program and the Howard Hughes Medical Institute. T.N.V. acknowledges support from a Ruth L. Kirschstein fellowship from the National Institute of Dental and Craniofacial Research (F31 DE023999).

Conflict of interest

No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Author information

Authors and Affiliations

  1. Department of Bioengineering, Rice University, MS 142, P.O. Box 1892, Houston, TX, 77251-1892, USA

    Jordan E. Trachtenberg, Tiffany N. Vo & Antonios G. Mikos

Authors
  1. Jordan E. Trachtenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiffany N. Vo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonios G. Mikos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonios G. Mikos.

Additional information

Associate Editors Rosemarie Hunziker oversaw the review of this article.

Jordan E. Trachtenberg and Tiffany N. Vo contributed equally to the preparation of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trachtenberg, J.E., Vo, T.N. & Mikos, A.G. Pre-clinical Characterization of Tissue Engineering Constructs for Bone and Cartilage Regeneration. Ann Biomed Eng 43, 681–696 (2015). https://doi.org/10.1007/s10439-014-1151-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-014-1151-0

Keywords

Search

Navigation