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Published Online: 6 October 2018

A Guide for Using Mechanical Stimulation to Enhance Tissue-Engineered Articular Cartilage Properties

Publication: Tissue Engineering Part B: Reviews
Volume 24, Issue Number 5

Abstract

The use of tissue-engineered articular cartilage (TEAC) constructs has the potential to become a powerful treatment option for cartilage lesions resulting from trauma or early stages of pathology. Although fundamental tissue-engineering strategies based on the use of scaffolds, cells, and signals have been developed, techniques that lead to biomimetic AC constructs that can be translated to in vivo use are yet to be fully confirmed. Mechanical stimulation during tissue culture can be an effective strategy to enhance the mechanical, structural, and cellular properties of tissue-engineered constructs toward mimicking those of native AC. This review focuses on the use of mechanical stimulation to attain and enhance the properties of AC constructs needed to translate these implants to the clinic. In vivo, mechanical loading at maximal and supramaximal physiological levels has been shown to be detrimental to AC through the development of degenerative changes. In contrast, multiple studies have revealed that during culture, mechanical stimulation within narrow ranges of magnitude and duration can produce anisotropic, mechanically robust AC constructs with high cellular viability. Significant progress has been made in evaluating a variety of mechanical stimulation techniques on TEAC, either alone or in combination with other stimuli. These advancements include determining and optimizing efficacious loading parameters (e.g., duration and frequency) to yield improvements in construct design criteria, such as collagen II content, compressive stiffness, cell viability, and fiber organization. With the advancement of mechanical stimulation as a potent strategy in AC tissue engineering, a compendium detailing the results achievable by various stimulus regimens would be of great use for researchers in academia and industry. The objective is to list the qualitative and quantitative effects that can be attained when direct compression, hydrostatic pressure, shear, and tensile loading are used to tissue-engineer AC. Our goal is to provide a practical guide to their use and optimization of loading parameters. For each loading condition, we will also present and discuss benefits and limitations of bioreactor configurations that have been used. The intent is for this review to serve as a reference for including mechanical stimulation strategies as part of AC construct culture regimens.

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References

1.
Afoke N., Byers P., and Hutton W. Contact pressures in the human hip joint. J Bone Joint Surg Br 69, 536, 1984.
2.
Eisenhart R., Adam C., Steinlechner M., and Eckstein F. Quantitative determination of joint incongruity and pressure distribution during simulated gait and cartilage thickness in the human hip joint. J Orthop Res 17, 532, 1999.
3.
Kalichman L., Li L., Kim D., et al. Facet joint osteoarthritis and low back pain in the community-based population. Spine (Phila. Pa. 1976) 33, 2560, 2011.
4.
Makris E., Gomoll A., Malizos K., Hu J., and Athanasiou K. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol 11, 21, 2014.
5.
Li K., Zhang C., Qiu L., Gao L., and Zhang X. Advances in application of mechanical stimuli in bioreactors for cartilage tissue engineering. Tissue Eng Part B Rev 23, 399, 2017.
6.
El-Ayoubi R., DeGrandpre C., DiRaddo R., and Yousefi A. Design and dynamic culture of 3D-scaffolds for cartilage tissue engineering. J Biomater Appl 25, 429, 2011.
7.
Mauck R., Nicoll S., Seyhan S., Ateshian G., and Hung C. Synergistic action of growth factors and dynamic loading for articular cartilage tissue engineering. Tissue Eng 9, 597, 2003.
8.
Natenstedt J., Kok A., Dankelman J., and Tuijthof G. What quantitative mechanical loading stimulates in vitro cultivation best? J Exp Orhtop 2, 1, 2015.
9.
FDA. Guidance for industry: preparation of IDEs and INDs for products intended to repair or replace knee cartilage. U.S. Food and Drug Administration, 2011.
10.
Grad S., Eglin D., Alini M., and Stoddart M. Physical stimulation of chondrogenic cells In vitro: a review. Clin Orthop Relat Res 469, 2764, 2011.
11.
Darling E., and Athanasiou K. Articular cartilage bioreactors and bioprocesses. Tissue Eng. 9, 9, 2003.
12.
Williamson A., Chen A., and Sah R. Compressive properties and function-composition relationships of developing bovine articular cartilage. J Orthop Res 19, 1113, 2001.
13.
Park S., Hung C., and Ateshian G. Mechanical response of bovine articular cartilage under dynamic unconfined compression loading at physiological stress levels. Osteoarthritis Cartilage 12, 65, 2004.
14.
Athanasiou K., Responte D., Brown W., and Hu J. Harnessing biomechanics to develop cartilage regeneration strategies. J Biomech Eng 137, 1, 2015.
15.
Athanasiou K., Darling E., Hu J., Durain G., and Reddi H. Articular Cartilage. Boca Raton, FL: CRC Press, LLC, 2017.
16.
Athanasiou K., Agarwal A., and Dzida F. Comparative study of the intrinsic mechanical properties of the human acetabular and femoral head cartilage. J Orthop Res 12, 340, 1994.
17.
Desrochers J., Amrein M., and Matyas J. Viscoelasticity of the articular cartilage surface in early osteoarthritis. Osteoarthrithis Cartilage 20, 413, 2012.
18.
Narmoneva D., Wang J., and Setton L. Nonuniform swelling-induced residual strains in articular cartilage. J Biomech 32, 401, 1999.
19.
Fan J., and Waldman S. The effect of intermittent static biaxial tensile strains on tissue engineered cartilage. Ann Biomed Eng 38, 1672, 2010.
20.
Wortman J., and Evans R. Young's modulus, shear modulus, and poisson's ratio in silicon and germanium. J Appl Phys 36, 153, 1965.
21.
Mansour J. Biomechanics of Cartilage. In Kinesiology: The Mechanics and Pathomechanics of Human Movement. Baltimore, MD: Wolters Kluwer Health, 2013, pp. 66–79.
22.
Williamson A., Chen A., Masuda K., and Sah R. Tensile mechanical properties of bovine articular cartilage: variations with growth and relationships to collagen network components. J Orhtop Res 21, 872, 2003.
23.
Eyre D. Collagen of articular cartilage. Arthritis Res 4, 30, 2001.
24.
Nieminen J. Effect of functional loading on remodelling in canine, and normal and collagen type II transgenic murine bone [PhD dissertation thesis]. Department of Anatomy and Institute of Clinical Medicine, University of Kuopio, Kuopio, Finland, 2009.
25.
Gelse K., Po E., and Aigner T. Collagens—structure, function, and biosynthesis. Adv Drug Deliv Rev 55, 1531, 2003.
26.
Viguet-carrin S., Garnero P., and Delmas P. The role of collagen in bone strength. Osteoporos Int 17, 319, 2006.
27.
Cissell D., Link J., Hu J., and Athanasiou K. A modified hydroxyproline assay based on hydrochloric acid in ehrlich's solution accurately measures tissue. Tissue Eng Part C Methods 23, 243, 2017.
28.
Roberts S., Menage J., Sandell L., Evans E., and Richardson J. Immunohistochemical study of collagen types I and II and procollagen IIA in human cartilage repair tissue following autologous chondrocyte implantation. Knee 5, 398, 2009.
29.
Eyre D., Weis M., and Wu J. Advances in collagen cross-link analysis. Methods 45, 65, 2008.
30.
Buckwalter J., and Mankin H. Articular cartilage: tissue design and chondrocyte-matrix interactions. Instr Course Lect 47, 477–486, 1998.
31.
Bayliss M., Osborne D., Woodhouse S., and Davidson C. Sulfation of chondroitin sulfate in human articular cartilage: the effect of age, topographical position, and zone of cartilage on tissue composition. J Bio Chem 274, 15892, 1999.
32.
Kuiper N., and Sharma A. A detailed quantitative outcome measure of glycosaminoglycans in human articular cartilage for cell therapy and tissue engineering strategies. Osteoarthritis Cartilage 23, 2233, 2015.
33.
Siebelt M., Groen H., Koelewijn S., et al. Increased physical activity severely induces osteoarthritic changes in knee joints with papain induced sulfate-glycosaminoglycan depleted cartilage. Arthritis Res Ther 16, 1, 2014.
34.
Farndale R., Buttle D., and Barrett A. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochem Biophys Acta 2, 173, 1986.
35.
Calabro A., Midura R., Wang A., West L., Plaas A., and Hascall V. Fluorophore-assisted carbohydrate electrophoresis (FACE) of glycosaminoglycans. Osteoarthrithis Cartilage 9, 16, 2001.
36.
Lin W., Chang Y., Wang H., et al. The study of the frequency effect of dynamic compressive loading on primary articular chondrocyte functions using a microcell culture system. Biomed Res Int 2014, 1, 2014.
37.
Van Susante L., Pieper J., Buma P., et al. Linkage of chondroitin-sulfate to type I collagen scaffolds stimulates the bioactivity of seeded chondrocytes in vitro. Biomaterials 22, 2359, 2001.
38.
Sophia Fox A., Bedi A., and Rodeo S. The basic science of articular cartilage: structure, composition, and function. Sports Health 1, 461, 2009.
39.
Silverberg J., Barrett A., Das M., Petersen P., Bonassar L., and Cohen I. Structure-function relations and rigidity percolation in the shear properties of articular cartilage. Biophys J 7, 1721, 2014.
40.
Stolz M., Raiteri R., Daniels A., Vanlandingham M., and Baschong W. Dynamic elastic modulus of porcine articular cartilage determined at two different levels of tissue organization by indentation-type atomic force microscopy. Biophys J 86, 3269, 2004.
41.
Fazaeli S., Ghazanfari S., Everts V., Smit T., and Koolstra J. The contribution of collagen fibers to the mechanical compressive properties of the temporomandibular joint disc. Osteoarthritis Cartilage 24, 1292, 2016.
42.
Jurvelin J., Buschmann M., and Hunziker E. Mechanical anisotropy of the human knee articular cartilage in compression. Proc Inst Mech Eng H 217, 215, 2003.
43.
Julkunen P., Jurvelin J., and Isaksson H. Contribution of tissue composition and structure to mechanical response of articular cartilage under different loading geometries and strain rates. Biomech Model Mechanobiol 9, 237, 2010.
44.
Peng G., McNary S., Athanasiou K., and Reddi H. Surface zone articular chondrocytes modulate the bulk and surface mechanical properties of the tissue-engineered cartilage. Tissue Eng Part A 20, 3332, 2045.
45.
Jay G., and Waller K. The biology of lubricin: near frictionless joint motion. Matrix Biol 39, 17, 2014.
46.
Schuurman W., Klein J., Dhert W., Van Weeren P., Hutmacher D., and Malda J. Cartilage regeneration using zonal chondrocyte subpopulations: a promising approach or an overcomplicated strategy? J Tissue Eng Regen Med 9, 669, 2015.
47.
Vanderploeg E., Wilson C., and Levenston M. Articular chondrocytes derived from distinct tissue zones differentially respond to in vitro oscillatory tensile loading. Osteoarthritis Cartilage 16, 1228, 2012.
48.
Mizuno S., and Ogawa R. Using changes in hydrostatic and osmotic pressure to manipulate metabolic function in chondrocytes. Am J Physiol Cell Physiol 300, 1234, 2011.
49.
Robins S., and Duncan A. Cross-linking of collagen: location of pyridinoline in bovine articular cartilage at two sites of the molecule. Biochem J 1, 175, 1983.
50.
McNerny E., Gardinier J., and Kohn D. Exercise increases pyridinoline cross-linking and counters the mechanical effects of concurrent lathyrogenic treatment. Bone 81, 327, 2015.
51.
Below S., Arnoczky S., Dodds J., Kooima C., and Walter N. The split-line pattern of the distal femur: a consideration in the orientation of autologous cartilage grafts. Arthroscopy 18, 613, 2002.
52.
Gruber H., and Wiggins W. Methods for transmission and scanning electron microscopy of bone and cartilage. In: An Y.H., Martin K.L., eds. Handbook of Histology Methods for Bone and Cartilage. Humana Press, 2003, pp. 497–504.
53.
Kienle S., Boettcher K., Wiegleb L., et al. Comparison of friction and wear of articular cartilage on different length scales. J Biomech 48, 3052, 2015.
54.
Chang D., Guilak F., Jay G., and Zauscher S. Interaction of lubricin with type II collagen surfaces: adsorption, friction, and normal forces. J Biomech 47, 659, 2014.
55.
Setton L., Zhu W., and Mow V. The biphasic poroviscoelasic behavior of articular cartilage role of the surface zone in governing the compressive behavior. J Biomech 26, 581, 1993.
56.
Gleghorn J.P., and Bonassar L. Lubrication mode analysis of articular cartilage using Stribeck surfaces. J Biomech 41, 1910, 2008.
57.
Atarod M., Ludwig T., Frank C., Schmidt T., and Shrive N. Cartilage boundary lubrication of ovine synovial fluid following anterior cruciate ligament transection: a longitudinal study. Osteoarthritis Cartilage 23, 640, 2015.
58.
Blum M., and Ovaert T. Low friction hydrogel for articular cartilage repair: evaluation of mechanical and tribological properties in comparison with natural cartilage tissue. Mater Sci Eng C Mater Biol Appl 33, 4377, 2013.
59.
Responte D., Lee J., Hu J., and Athanasiou K. Biomechanics-driven chondrogenesis: from embryo to adult. FASEB J 26, 3614, 2017.
60.
Roddy K., Prendergast P., and Murphy P. Mechanical influences on morphogenesis of the knee joint revealed through morphological, molecular and computational analysis of immobilised embryos. PLoS One 6, e17526, 2011.
61.
Hall B., and Herring S. Paralysis and growth of the musculoskeletal system in the embryonic chick. J Morphol 206, 45, 1990.
62.
Nowlan N., Sharpe J., Roddy K., Prendergast P., and Murphy P. Mechanobiology of embryonic skeletal development: insights from animal models. Birth Defects Res C Embryo Today 90, 203, 2010.
63.
Kisiday J., Jin M., Dimicco M., Kurz B., and Grodzinsky A. Effects of dynamic compressive loading on chondrocyte biosynthesis in self-assembling peptide scaffolds. J Biomech 37, 595, 2004.
64.
Nebelung S., Gavenis K., Lüring C., et al. Simultaneous anabolic and catabolic responses of human chondrocytes seeded in collagen hydrogels to long-term continuous dynamic compression. Ann Anat 194, 351, 2012.
65.
Shahin K., and Doran P. Tissue engineering of cartilage using a mechanobioreactor exerting simultaneous mechanical shear and compression to simulate the rolling action of articular joints. Biotechnol Bioeng 109, 1060, 2012.
66.
Elder B., and Athanasiou K. Effects of confinement on the mechanical properties of self-assembeled articular cartilage constructs in the direction orthogonal to the confinement surface. J Orthop Res 26, 238, 2008.
67.
Huwe L., Sullan G., Hu J.C., and Athanasiou K. Using costal chondrocytes to engineer articular cartilage with applications of passive axial compression and bioactive stimuli. Tissue Eng Part A 24(5–6), 516, 2018.
68.
Suh J. Dynamic unconfined compression of articular cartilage under a cyclic compressive load. Biorheology 33, 289304, 1996.
69.
Tran S., Cooley A., and Elder S. Effect of a mechanical stimulation bioreactor on tissue engineered, scaffold-free cartilage. Biotechnol Bioeng 108, 1421, 2011.
70.
Correia C., Pereira A., Duarte A., Frias A., Pedro A., and Oliveira T. Dynamic culturing of cartilage tissue: the significance of hydrostatic pressure. Tissue Eng Part A 18, 1979, 2012.
71.
Mauck R., Soltz M., Wang C., Wong D., Chao P., and Ateshian G. Functional tissue engineering of articular cartilage through dynamic loading of chondrocyte-seeded agarose gels. J Biomech Eng 122, 252, 2000.
72.
MacBarb R., Paschos N., Abeug R., Makris E., Hu J., and Athanasiou K. Passive strain-induced matrix synthesis and organization in shape-specific, cartilaginous neotissues. Tissue Eng Part A 20, 3290, 2014.
73.
Gemmiti C., and Guldberg R. Fluid flow increases type II collagen deposition and tissue-engineered cartilage. Tissue Eng 12, 7, 2006.
74.
Gemmiti C., and Guldberg R. Shear stress magnitude and duration modulates matrix composition and tensile mechanical properties in engineered cartilaginous tissue. Biotechnol Bioeng 104, 809, 2010.
75.
Grad S., Loparic M., Peter R., Stolz M., Aebi U., and Alini M. Sliding motion modulates stiffness and friction coefficient at the surface of tissue engineered cartilage. Osteoarthritis Cartilage 20, 288, 2012.
76.
Stoddart M., Ettinger L., Jo H., and Zu C. Enhanced matrix synthesis in de novo, scaffold free cartilage-like tissue subjected to compression and shear. Biotechnol Bioeng 95, 1043, 2006.
77.
Yusoff N., Azuan N., Osman A., and Pingguan-murphy B. Design and validation of a bi-axial loading bioreactor for mechanical stimulation of engineered cartilage. Med Eng Phys 33, 782, 2011.
78.
Sun M., Lv D., Zhang C., and Zhu L. Culturing functional cartilage tissue under a novel bionic mechanical condition. Med Hypotheses 75, 657, 2010.
79.
Zhu G., Mayer-wagner S., Schröder C., et al. Comparing effects of perfusion and hydrostatic pressure on gene profiles of human chondrocyte. J Biotechnol 210, 59, 2015.
80.
Freyria A., Cortial D., Ronziere M., Guerret S., and Herbage D. Influence of medium composition, static and stirred conditions on the proliferation of and matrix protein expression of bovine articular chondrocytes cultured in a 3-D collagen scaffold. Biomaterials 25, 687, 2004.
81.
Zhao J., Griffin M., Cai J., Li S., Bulter P., and Kalaskar D. Bioreactors for tissue engineering: an update. Biochem Eng J 109, 268, 2016.
82.
Gharravi A., Orazizadeh M., Ansari-asl K., and Banoni S. Design and fabrication of anatomical bioreactor systems containing alginate scaffolds for cartilage tissue engineering. Avicenna J Med Biotechnol 4, 65, 2012.
83.
Di Federico E., Bader D., and Shelton J. Design and validation of an in vitro loading system for the combined application of cyclic compression and shear to 3D chondrocytes-seeded agarose constructs. Med Eng Phys 36, 534, 2014.
84.
Bian L., Fong J., Lima E., Stoker A., Ateshian G., and Cook J. Dynamic mechanical loading enhances functional properties of tissue-engineered cartilage using mature canine chondrocytes. Tissue Eng Part A 16, 1781, 2010.
85.
Waldman S., Spiteri C., Grynpas M., Pilliar R., and Kandel R. Long-term intermittent shear deformation improves the quality of cartilaginous tissue formed in vitro. J Orthop Res 21, 590, 2003.
86.
Gleghorn J., Jones A., Flannery C., and Bonassar L. Alteration of articular cartilage frictional properties by transforming growth factor-beta, interleukin-1Beta, and oncostatin M. Arthritis Rheum 60, 440, 2009.
87.
Wimmer M., Alini M., and Grad S. The effect of sliding velocity on chondrocytes activity in 3D scaffolds. J Biomech 42, 424, 2009.
88.
Theodoropoulos J., DeCroos A., Petrera M., Park S., and Kandel R. Mechanical stimulation enhances integration in an in-vitro model of cartilage repair. Knee Surg Sport Traumatol Arthosc 24, 2055, 2016.
89.
Pei Y., Fan J., Zhang X., Zhang Z., and Yu M. Repairing the osteochondral defect in goat with the tissue-engineered osteochondral graft preconstructed in a double-chamber stirring bioreactor. Biomed Res Int 2014, 1, 2014.
90.
Elder B., and Athanasiou K. Hydrostatic pressure in articular cartilage tissue engineering: from chondrocytes to tissue regeneration. Tissue Eng Part B Rev 15, 43, 2009.
91.
Smith L., Lin J., Trindade M., Shida J., and Kajiyama G. Time-dependent effects of intermittent hydrostatic pressure on articular chondrocyte type II collagen and aggrecan mRNA expression. J Rehabil Res Dev 37, 153, 2000.
92.
Smith L., Rusk S., Ellison B., Wessels P., Tsuchiya K., and Carter D. In vitro stimulation of articular chondrocyte mRNA and extracellular matrix synthesis by hydrostatic pressure. J Orthop Res 14, 53, 1996.
93.
Heyland J., Wiegandt K., Goepfert C., Scumacher U., and Portner R. Redifferentiation of chondrocytes and cartilage formation under intermittent hydrostatic pressure. Biotechnol Lett 28, 1641, 2006.
94.
Gunja N., and Athanasiou K. Effects of hydrostatic pressure on leporine meniscus cell-seeded PLLA scaffolds. J Biomed Mater Res A. 92A, 896, 2010.
95.
Chen J., Yuan Z., Liu Y., Zheng R., Dai Y., and Tao R. Improvement of in vitro three-dimensional cartilage regeneration by a novel hydrostatic pressure bioreactor. Stem Cells Transl Med 6, 982, 2017.
96.
Parkkinen J., Lammi M., Pelttari A., Helminen H., Tammi M., and Virtanen I. Altered golgi apparatus in hydrostatically loaded articular cartilage chondrocytes. Ann Rheum Dis 52, 192, 1993.
97.
Hu J., and Athanasiou K. The effects of intermittent hydrostatic pressure on self-assembled articular cartilage constructs. Tissue Eng 12, 1337, 2006.
98.
Gunja N., Uthamathil R., and Athanasiou K. Effects of TGF-beta1 and hydrostatic pressure on mensicus cell-seeded scaffolds. Biomaterials 30, 565, 2009.
99.
Huang B., Hu J., and Athanasiou K. Cell-based tissue engineering strategies used in the clinical repair of articular cartilage. Biomaterials 98, 1, 2016.
100.
Mizuno S., Kusanagi A., Tarrant L., Tokuno T., and Smith R. System useful for repairing cartilage, comprises lyophilized acellular collagen matrix containing pores and bioactive agent disposed within the pores patent. United States patent US20130273121A1. 2013.
101.
Elder B., and Athanasiou K. Effects of temporal hydrostatic pressure on tissue-engineered bovine articular cartilage constructs. Tissue Eng Part A Part A 15, 1151, 2009.
102.
Elder B., and Athanasiou K. Synergistic and additive effects of hydrostatic pressure and growth factors on tissue formation. PLoS One 3, e2341, 2008.
103.
Kraft J., Jeong C., Novotny J., et al. Effects of hydrostatic loading on a self-aggregating, suspension culture-derived cartilage tissue analog. Cartilage 2, 254, 2011.
104.
Lee J., Huwe L., Paschos N., et al. Tension stimulation drives tissue formation in scaffold-free systems. Nat Mater 16, 864, 2017.
105.
Wu S., Wang Y., Streubel P., and Duan B. Living nanofiber yarn-based woven biotextiles for tendon tissue engineering using cell triculture and mechanical stimulation. Acta Biomater 62, 102, 2017.
106.
Bieler F., Ott C., Thompson M., et al. Biaxial cell stimulation: a mechanical validation. J Biomech 42, 1692, 2009.
107.
Wartella K., and Wayne J. Bioreactor for biaxial mechanical stimulation to tissue engineered constructs. J Biomech Eng 131, 1, 2017.
108.
Vanderploeg E.J., Imler S.M., Brodkin K.R., Garcia A.J., et al. Oscillitory tension differentially modulates matrix metabolism and cytoskeletal organization in chondroctyes and fibrochondrocytes. J Biomech 37, 1913, 2004.
109.
Connelly J.T., Wilson C.G., and Levenston M.E. Characterization of proteoglycan production and processing by chondrocytes and BMSCs in tissue engineered constructs. Osteoarthr Cartil 16, 1228, 2008.

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cover image Tissue Engineering Part B: Reviews
Tissue Engineering Part B: Reviews
Volume 24Issue Number 5October 2018
Pages: 345 - 358
PubMed: 29562835

History

Published online: 6 October 2018
Published in print: October 2018
Published ahead of print: 26 April 2018
Published ahead of production: 21 March 2018
Accepted: 21 March 2018
Received: 8 January 2018

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Evelia Y. Salinas
Biomedical Engineering Department, University of California, Irvine, California.
Jerry C. Hu
Biomedical Engineering Department, University of California, Irvine, California.
Kyriacos Athanasiou [email protected]
Biomedical Engineering Department, University of California, Irvine, California.

Notes

Address correspondence to:Kyriacos Athanasiou, PhDBiomedical Engineering DepartmentUniversity of CaliforniaIrvine,CA 92616 [email protected]

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No competing financial interests exist.

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