Top-Down and Bottom-Up Engineered Microenvironments for Cartilage Tissue Regeneration

Tissue engineering has the potential to mitigate and remedy many degenerative diseases and traumatic injuries. Osteoarthritis, characterized by the structural and biochemical degradation of articular cartilage, affects over 27 million individuals nationwide. The current clinical standard for cartilage repair includes methods such as mosaicplasty and autograft transplantation, where cartilage from non-load bearing regions is used to fill in defects in the cartilage structure. These methods suggest that the complex structure and biochemistry of native cartilage extracellular matrix positively contributes to cartilage healing and regeneration. We investigated this idea through a series of top-down and bottom-up tissue engineering approaches. Using a top-down approach, we studied the healing capability of decellularized cartilage allografts in an in vivo ovine osteoarthritis model. The results of this in vivo study showed positive cartilage healing and supported the model of tissue physicochemical microenvironment as an ideal environment for tissue regeneration. As a result, we investigated a bottom-up approach, attempting to recapitulate various aspects of the native cartilage tissue. In the first study, we investigated the ability of polymerizable collagen fibrils to be aligned in the presence of high magnetic fields, emulating the fibril alignment aspect of the cartilage superficial zone. Further, using a plastic compression approach, we developed gradient collagen structures that emulated the depth dependent alignment properties of articular cartilage while greatly increasing the density and mechanical properties. Finally, we combined the top-down and bottom-up approaches in a unique way to introduce native cartilage signals to a stem cell population. Microparticulated and decellularized cartilage was introduced to collagen-suspended human mesenchymal stem cells in a 3D composite matrix. Additional composites formed from Gu·HCl reductions gave further insight into the contribution of the various ECM components of articular cartilage on the differentiation potential of human MSCs for cartilage regeneration. The culmination of these studies gives unique information on the separation and combination of top-down and bottom-up approaches to tissue engineering in the field of cartilage and osteoarthritis.

Year	Entry
2002	Davisson T, Kunig S, Chen A, Sah R, Ratcliffe A. Static and dynamic compression modulate matrix metabolism in tissue engineered cartilage. J Orthop Res. July 2002;20(4):842-848.
1992	Mow VC, Ratcliffe A, Robin Poole A. Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials. 1992;13(22):67-97.
2002	Mow VC, Guo XE. Mechano-electrochemical properties of articular cartilage: their inhomogeneities and anisotropies. Annu Rev Biomed Eng. 2002;4:175-209.
2010	Doube M, Kłosowski MM, Arganda-Carreras I, Cordelières FP, Dougherty RP, Jackson JS, Schmid B, Hutchinson JR, Shefelbine SJ. BoneJ: free and extensible bone image analysis in ImageJ. Bone. December 2010;47(6):1076-1079.
2007	Moutos FT, Freed LE, Guilak F. A biomimetic three-dimensional woven composite scaffold for functional tissue engineering of cartilage. Nat Mater. February 2007;6(2):162-167.
2003	Mauck RL, Wang CC-B, Oswald ES, Ateshian GA, Hung CT. The role of cell seeding density and nutrient supply for articular cartilage tissue engineering with deformational loading. Osteoarthritis Cartilage. December 2003;11(12):879-890.
2007	Khalafi A, Schmid TM, Neu C, Reddi AH. Increased accumulation of superficial zone protein (SZP) in articular cartilage in response to bone morphogenetic protein-7 and growth factors. J Orthop Res. March 2007;25(3):293-303.
1991	Lai WM, Hou JS, Mow VC. A triphasic theory for the swelling and deformation behaviors of articular cartilage. J Biomech Eng. August 1991;113(3):245-258.
2007	Schmidt TA, Gastelum NS, Nguyen QT, Schumacher BL, Sah RL. Boundary lubrication of articular cartilage: role of synovial fluid constituents. Arthritis Rheum. March 2007;56(3):882-891.
2002	Korhonen RK, Laasanen MS, Töyräs J, Rieppo J, Hirvonen J, Helminen HJ, Jurvelin JS. Comparison of the equilibrium response of articular cartilage in unconfined compression, confined compression and indentation. J Biomech. July 2002;35(7):903-909.
2012	Huey DJ, Hu JC, Athanasiou KA. Unlike bone, cartilage regeneration remains elusive. Science. November 16, 2012;338(6109):917-921.
1998	Quinn TM, Grodzinsky AJ, Hunziker EB, Sandy JD. Effects of injurious compression on matrix turnover around individual cells in calf articular cartilage explants. J Orthop Res. July 1998;16(4):490-499.
2003	Thomopoulos S, Williams GR, Gimbel JA, Favata M, Soslowsky LJ. Variation of biomechanical, structural, and compositional properties along the tendon to bone insertion site. J Orthop Res. May 2003;21(3):413-419.
2006	Mauck RL, Yuan X, Tuan RS. Chondrogenic differentiation and functional maturation of bovine mesenchymal stem cells in long-term agarose culture. Osteoarthritis Cartilage. February 2006;14(2):179-189.
1994	Hollander AP, Heathfield TF, Webber C, Iwata Y, Bourne R, Rorabeck C, Poole AR. Increased damage to type II collagen in osteoarthritic articular cartilage detected by a new immunoassay. J Clin Invest. April 1994;93(4):1722-1732.
1999	Vunjak-Novakovic G, Martin I, Obradovic B, Treppo S, Grodzinsky AJ, Langer R, Freed LE. Bioreactor cultivation conditions modulate the composition and mechanical properties of tissue-engineered cartilage. J Orthop Res. January 1999;17(1):130-138.
2004	Awad HA, Wickham MQ, Leddy HA, Gimble JM, Guilak F. Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds. Biomaterials. July 2004;25(16):3211-3222.
1994	Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. NEJM. October 6, 1994;331(14):889-895.
2006	Pritzker KPH, Gay S, Jimenez SA, Ostergaard K, Pelletier J-P, Revell PA, Salter D, van den Berg WB. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage. January 2006;14(1):13-29.
2007	Klein TJ, Chaudhry M, Bae WC, Sah RL. Depth-dependent biomechanical and biochemical properties of fetal, newborn, and tissue-engineered articular cartilage. J Biomech. January 2007;40(1):182-190.
2006	Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. August 25, 2006;126(4):P677-P689.

Year

Entry

2002

Davisson T, Kunig S, Chen A, Sah R, Ratcliffe A. Static and dynamic compression modulate matrix metabolism in tissue engineered cartilage. J Orthop Res. July 2002;20(4):842-848.

1992

Mow VC, Ratcliffe A, Robin Poole A. Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials. 1992;13(22):67-97.

2002

Mow VC, Guo XE. Mechano-electrochemical properties of articular cartilage: their inhomogeneities and anisotropies. Annu Rev Biomed Eng. 2002;4:175-209.

2010

Doube M, Kłosowski MM, Arganda-Carreras I, Cordelières FP, Dougherty RP, Jackson JS, Schmid B, Hutchinson JR, Shefelbine SJ. BoneJ: free and extensible bone image analysis in ImageJ. Bone. December 2010;47(6):1076-1079.

2007

Moutos FT, Freed LE, Guilak F. A biomimetic three-dimensional woven composite scaffold for functional tissue engineering of cartilage. Nat Mater. February 2007;6(2):162-167.