Bioprinting of osteochondral tissues: A perspective on current gaps and future trends

Pallab Datta, Aman Dhawan, Yin Yu, Dan Hayes, Hemanth Gudapati, Ibrahim Tarik Ozbolat

Article ID: 111
Vol 3, Issue 2, 2017, Article identifier:109-120

VIEWS - 2118 (Abstract) 660 (PDF)


Osteochondral tissue regeneration has remained a critical challenge in orthopaedic surgery, especially due to complications of arthritic degeneration arising out of mechanical dislocations of joints. The common gold standard of autografting has several limitations in presenting tissue engineering strategies to solve the unmet clinical need. However, due to the complexity of joint anatomy, and tissue heterogeneity at the interface, the conventional tissue engineering strategies have certain limitations. The advent of bioprinting has now provided new opportunities for osteochondral tissue engineering. Bioprinting can uniquely mimic the heterogeneous cellular composition and anisotropic extracellular matrix (ECM) organization, while allowing for targeted gene delivery to achieve heterotypic differentiation. In this perspective, we discuss the current advances made towards bioprinting of composite osteochondral tissues and present an account of challenges—in terms of tissue integration, long-term survival, and mechanical strength at the time of implantation—required to be addressed for effective clinical translation of bioprinted tissues. Finally, we highlight some of the future trends related to osteochondral bioprinting with the hope of in-clinical translation.


bioprinting; osteochondral injuries; zonal anisotropy; bioink; tissue engineering

Full Text:



Lories R J and Luyten F P, 2011, The bone–cartilage unit in osteoarthritis. Nature Reviews Rheumatology, vol.7: 43–49.

Stephens R L, Yang H, Rivier J, et al., 1988, Intracisternal injection of CRF antagonist blocks surgical stress-induced inhibition of gastric secretion in the rat. Peptides, vol.9(5): 1067–1070.

Buckwalter J and Lappin D R, 2000, The disproportionate impact of chronic arthralgia and arthritis among women. Clinical Orthopaedics and Related Research, vol.52: 159–168.

Bitton R, 2009, The economic burden of osteoarthritis. American Journal Managed Care, vol.15: S230–S235.

Makris E A, Gomoll A H, Malizos K N, et al., 2014, Repair and tissue engineering techniques for articular cartilage. Nature Reviews Rheumatology, vol.11: 21–34.

Nukavarapu S P and Dorcemus D L, 2013, Osteochondral tissue engineering: Current strategies and challenges. Biotechnology Advances, vol.31: 706–721.

Jeon J E, Vaquette C, Klein T J, et al., 2014, Perspectives in multiphasic osteochondral tissue engineering. The Anatomical Record, vol.297: 26–35.

Gadjanski I and Vunjak-Novakovic G, 2015, Challenges in engineering osteochondral tissue grafts with hierarchical structures. Expert Opinion on Biological Therapy., vol.15: 1583–1599.

Grayson W L, Chao P-H G, Marolt D, et al., 2008, Engineering custom-designed osteochondral tissue grafts. Trends in Biotechnology, vol.26: 181–189.

Ofek G and Athanasiou K A, 2007, Micromechanical properties of chondrocytes and chondrons: Relevance to articular cartilage tissue engineering. Journal of Mechanics of Materials and Structures, vol.2: 1059–1086.

Heller M, Bauer HK, Goetze E, et al., 2016, Materials and scaffolds in medical 3D printing and bioprinting in the context of bone regeneration. International Journal of Computerized Dentistry, vol.19(4): 301–321.

Henkel J, Woodruff M A, Epari D R, et al., 2013, Bone regeneration based on tissue engineering conceptions – A 21st century perspective. Bone Research, vol.3: 216–248.

Aigner T, Rose J, Martin J, et al., 2004, Aging theories of primary osteoarthritis: From epidemiology to molecular biology. Rejuvenation Research, vol.7: 134–145.

Zhang L, Hu J and Athanasiou K A, 2009, The role of tissue engineering in articular cartilage repair and regeneration. Critical ReviewsTM in Biomedical Engineering, vol.37(1–2): 1–57.

Temenoff J S and Mikos A G, 2000, Review: Tissue engineering for regeneration of articular cartilage. Biomaterials, vol.21: 431–440.

Farr J, Cole B, Dhawan A, et al., 2011, Clinical cartilage restoration: Evolution and overview. Clinical Orthopaedics and Related Research, vol.469: 2696–2705.

Cole B J, Pascual-Garrido C and Grumet R C, 2009, Surgical management of articular cartilage defects in the knee. Journal of Bone & Joint Surgery – American Volume, vol.91(7): 1778–1790.

Gomoll A H, Madry H, Knutsen G, et al., 2010, The subchondral bone in articular cartilage repair: Current problems in the surgical management. Knee Surgery, Sports Traumatology and Arthroscopy, vol.18: 434–447.

Mastbergen S C, Saris D B F and Lafeber F P J G, 2013, Functional articular cartilage repair: Here, near, or is the best approach not yet clear? Nature Reviews Rheumatology, vol.9: 277–290.

Carey J G and Grimm N L, 2015, Treatment algorithm for osteochondritis dissecans of the knee. Orthopaedics Clinics of North America, vol.46(1): 141–146.

Carey J L and Grimm N L, 2014, Treatment algorithm for osteochondritis dissecans of the knee. Clinical Sports Medicines, vol.33: 375–382.

Polousky J D and Albright J, 2014, Salvage techniques in osteochondritis dissecans. Clinical Sports Medicines, vol.33: 321–333.

Gallo R A, Plakke M, Mosher T, et al., 2016, Outcomes following impaction bone grafting for treatment of unstable osteochondritis dissecans. The Knee, vol.23: 495–500.

Torrie A M, Kesler W W, Elkin J, et al., 2015, Osteochondral allograft. Current Reviews in Musculoskeletal Medicines, vol.8(4): 413–422.

Verhaegen J, Clockaerts S, Van Osch G J V M, et al., 2014, TruFit Plug for repair of osteochondral defects—Where is the evidence? Systematic review of literature. Cartilage, vol.6: 12–19.

Kon E, Filardo G, Di Martino A, et al., 2013, Clinical results and MRI evolution of a nano-composite multilayered biomaterial for osteochondral regeneration at 5 years. American Journal of Sports Medicine, vol.42: 158–165.

Levy Y D, Gorts S, Pulido P A, et al., 2013, Do fresh osteochondral allograft successfully treat femoral condyle lesions? Clinical Orthopaedics and Related Research, vol.471(1): 231–237.

Appelman T P, Mizrahi J, Elisseeff J H, et al., 2011, The influence of biological motifs and dynamic mechanical stimulation in hydrogel scaffold systems on the phenotype of chondrocytes. Biomaterials, vol.32: 1508–1516.

Johnstone B and Yoo J, 2001, Mesenchymal cell transfer for articular cartilage repair. Experts Opinion on Biological Therapy, vol.1(6): 915–921.

Koga H, Engebretsen L, Brinchmann J E, et al., 2009, Mesenchymal stem cell-based therapy for cartilage repair: A review. Knee Surgery, Sports Traumatology, Arthroscopy, vol.17: 1289–1297.

Park S and Im G, 2014, Embryonic stem cells and induced pluripotent stem cells for skeletal regeneration. Tissue Engineering Part B: Reviews, vol.20(5): 1–11.

Diekman B O, Christoforou N, Willard V P, et al., 2012, Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells. Proceedings of the National Academic of Sciences, vol.109: 19172–19177.

Yu Y, Brouillette M J, Seol D, et al., 2015, Use of recombinant human stromal cell-derived factor 1 α-loaded fibrin/hyaluronic acid hydrogel networks to achieve functional repair of full-thickness bovine articular cartilage via homing of chondrogenic progenitor cells. Arthritis & Rheumatology, vol.67(5): 1274–1285.

Ringe J, Burmester G R, Sittinger M, et al., 2012, Regenerative medicine in rheumatic disease—Progress in tissue engineering. Nature Reviews Rheumatology, vol.8: 493–498.

Ozbolat I T, 2015, Scaffold-based or scaffold-free bioprinting: Competing or complementing approaches? Journal of Nanotechnology in Engineering and Medicine, vol.6: 24701.

Niederauer G G, Slivka M A, Leatherbury N C, et al., 2000, Evaluation of multiphase implants for repair of focal osteochondral defects in goats. Biomaterials, vol.21: 2561–2574.

Schlichting K, Schell H, Kleemann R U, et al., 2008, Influence of scaffold stiffness on subchondral bone and subsequent cartilage regeneration in an ovine model of osteochondral defect healing. American Journal of Sports Medicine, vol.36: 2379–2391.

Jiang C-C, Chiang H, Liao C-J, et al., 2007, Repair of porcine articular cartilage defect with a biphasic osteochondral composite. Journal of Orthopaedic Research, vol.25: 1277–1290.

Schagemann J C, Erggelet C, Chung H-W, et al., 2008, Cell-laden and cell-free biopolymer hydrogel for the treatment of osteochondral defects in a sheep model. Tissue Engineering Part A, vol.15(1): 75–82.

Kon E, Filardo G, Perdisa F, et al., 2014, Clinical results of multilayered biomaterials for osteochondral regeneration. Journal of Experimental Orthopaedics, vol.1: 10.

Quarch V M A, Enderle E, Lotz J, et al., 2014, Fate of large donor site defects in osteochondral transfer procedures in the knee joint with and without TruFit Plugs. Archives of Orthopaedic and Trauma Surgery, vol.134(5): 657–666.

Gelber P E, Batista J, Millan-Billi A, et al., 2014, Magnetic resonance evaluation of TruFit® plugs for the treatment of osteochondral lesions of the knee shows the poor characteristics of the repair tissue. The Knee, vol.21: 827–832.

Meyer U, Wiesmann H P, Libera J, et al., 2012, Cartilage defect regeneration by ex vivo engineered autologous microtissue—Preliminary results. In Vivo, vol.26(2): 251–257.

Makris E A, Gomoll A H, Malizos K N, et al., 2015, Repair and tissue engineering techniques for articular cartilage. Nature Reviews Rheumatology, vol.11(1): 21–34.

Schek R M, Taboas J M, Segvich S J, et al., 2004, Engineered osteochondral grafts using biphasic composite solid free-form fabricated scaffolds. Tissue Engineering, vol.10: 1376–1385.

Zhang W, Lian Q, Li D, et al., 2014, Cartilage repair and subchondral bone migration using 3D printing osteochondral composites: A one-year-period study in rabbit trochlea. BioMed Research International, vol.2014: 746138.

Cao T, Ho K-H and Teoh S-H, 2003, Scaffold design and in vitro study of osteochondral coculture in a three-dimensional porous polycaprolactone scaffold fabricated by fused deposition modeling. Tissue Engineering, vol.9(Suppl 1): S103–S112.

Nowicki M A, Castro N J, Plesniak M W, et al., 2016, 3D printing of novel osteochondral scaffolds with graded microstructure. Nanotechnology, vol.27: 414001.

Castro N J, Patel R and Zhang L G, 2015, Design of a novel 3D printed bioactive nanocomposite scaffold for improved osteochondral regeneration. Cellular and Molecular Bioengineering, vol.8: 416–432.

Shao X X, Hutmacher D W, Ho S T, et al., 2006, Evaluation of a hybrid scaffold/cell construct in repair of high-load-bearing osteochondral defects in rabbits. Biomaterials, vol.27: 1071–1080.

Cho D-W, Lee J-S, Jang J, et al., 2015, Tissue engineering: Osteochondral tissue, In: Organ Printing, Bristol, UK: Morgan & Claypool Publishers, 11.1–11.6.

Chua C K, Leong K F, Sudarmadji N, et al., 2011, Selective laser sintering of functionally graded tissue scaffolds. MRS Bulletin, vol.36(12): 1006–1014.

Du Y, Liu H, Yang Q, et al., 2017, Selective laser sintering scaffold with hierarchical architecture and gradient composition for osteochondral repair in rabbits. Biomaterials, vol.137: 37–48.

Ozbolat I T, Peng W and Ozbolat V, 2016, Application areas of 3D bioprinting. Drug Discovery Today, vol.21: 1257–1271.

Ozbolat I T, Moncal K K and Gudapati H, 2017, Evaluation of bioprinter technologies. Additive Manufacturing, vol.13: 179–200.

Ozbolat I T and Hospodiuk M, 2016, Current advances and future perspectives in extrusion-based bioprinting. Biomaterials, vol.76: 321–343.

Gudapati H, Dey M and Ozbolat I T, 2016, A comprehensive review on droplet-based bioprinting: Past, present and future. Biomaterials, vol.102: 20–42.

Ozbolat I T, 2015, Bioprinting scale-up tissue and organ constructs for transplantation. Trends in Biotechnology, vol.33: 395–400.

Dababneh A B and Ozbolat I T, 2014, Bioprinting technology: A current state-of-the-art review. Journal of Manufacturing Science and Engineering, vol.136(6): 61016.

Datta P, Ayan B and Ozbolat I T, 2017, Bioprinting for vascular and vascularized tissue biofabrication. Acta Biomaterialia, vol.51: 1–20.

Ozbolat I T and Yu Y, 2013, Bioprinting toward organ fabrication: Challenges and future trends. IEEE Transactions on Biomedical Engineering, vol.60: 60691–60699.

Fedorovich N E, Schuurman W, Wijnberg H M, et al., 2011, Biofabrication of osteochondral tissue equivalents by printing topologically defined, cell-laden hydrogel scaffolds. Tissue Engineering Part C: Methods, vol.18: 33–44.

Park J Y, Choi J C, Shim J H, et al., 2014, A comparative study on collagen type I and hyaluronic acid dependent cell behavior for osteochondral tissue bioprinting. Biofabrication, vol.6(3): 35004.

Gurkan U A, El Assal R, Yildiz S E, et al., 2014, Engineering anisotropic biomimetic fibrocartilage microenvironment by bioprinting mesenchymal stem cells in nanoliter gel droplets. Molecular Pharmacology, vol.11: 2151–2159.

Levato R, Visser J, Planell J A, et al., 2014, Biofabrication of tissue constructs by 3D bioprinting of cell-laden microcarriers. Biofabrication, vol.6: 35020.

Sawkins M J, Brown B N, Bonassar L J, et al., 2011, Bioprinting as a tool for osteochondral tissue engineering. European Cells and Materials, vol.22: 51.

Aydelottea M, Greenhill R and Kuettnerab K, 1988, Differences between sub-populations of cultured bovine articular chondrocytes. II. Proteoglycan metabolism. Connective Tissue Research, vol.18(3): 223–234.

Neu C P, Komvopoulos K and Reddi A H, 2008, The interface of functional biotribology and regenerative medicine in synovial joints. Tissue Engineering Part B: Reviews, vol.14(3): 235–247.

Clark J M and Huber J D, 1990, The structure of the human subchondral plate. Journal of Bone & Joint Surgery – British Volume, vol.72(5): 866–873.

MacBarb R F, Chen A L, Hu J C, et al., 2013, Engineering functional anisotropy in fibrocartilage neotissues. Biomaterials, vol.34: 9980–9989.

Hu J C Y and Athanasiou K A, 2003, Structure and function of articular cartilage, In: An YH and Martin KL (editors), Handbook of Histology Methods in Bone and Cartilage. Totowa, NJ, USA: Humana Press. 73–95.

Mouser V H M, Levato R, Bonassar L J, et al., 2016, Three-dimensional bioprinting and its potential in the field of articular cartilage regeneration. Cartilage, 1–14.

Kelly D J and Prendergast P J, 2006, Prediction of the optimal mechanical properties for a scaffold used in osteochondral defect repair. Tissue Engineering, vol.12: 2509–2519.

Shim J-H, Jang K-M, Hahn S K, et al., 2016, Three-dimensional bioprinting of multilayered constructs containing human mesenchymal stromal cells for osteochondral tissue regeneration in the rabbit knee joint. Biofabrication, vol.8: 14102.

Shim J, Lee J, Kim J, et al., 2012, Bioprinting of a mechanically enhanced three-dimensional dual cell-laden construct for osteochondral tissue engineering using a multi-head tissue/organ building. Journal of Micromechanics and Microengineering, vol.22(8): 85014.

Liu Y-Y, Yu H-C, Liu Y, et al., 2016, Dual drug spatiotemporal release from functional gradient scaffolds prepared using 3D bioprinting and electrospinning. Polymer Engineering and Science, vol.56(2): 170–177.

Radhakrishnan J, Subramanian A, Krishnan U M, et al., 2017, Injectable and 3D bioprinted polysaccharide hydrogels: From cartilage to osteochondral tissue engineering. Biomacromolecules, vol.18: 1–26.

Luzi E, Marini F, Sala S C, et al., 2008, Osteogenic differentiation of human adipose tissue-derived stem cells is modulated by the miR-26a targeting of the SMAD1 transcription factor. Journal of Bone and Mineral Research, vol.23(2): 287–295.

Schoolmeesters A, Eklund T, Leake D, et al., 2009, Functional profiling reveals critical role for miRNA in differentiation of human mesenchymal stem cells. PLoS One, vol.4: e5605.

Mizuno Y, Yagi K, Tokuzawa Y, et al., 2008, miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochemical and Biophysics Research Communication, vol.368: 267–272.

Mendonça R H, de Oliveira Meiga T, da Costa M F, et al., 2013, Production of 3D scaffolds applied to tissue engineering using chitosan swelling as a porogenic agent. Journal of Applied Polymer Science, vol.129(2): 614–625.

Qureshi A T, Doyle A, Chen C, et al., 2015, Photoactivated miR-148b–nanoparticle conjugates improve closure of critical size mouse calvarial defects. Acta Biomaterialia, vol.12: 166–173.

Qureshi A T, Monroe W T, Dasa V, et al., 2013, miR-148b–nanoparticle conjugates for light mediated osteogenesis of human adipose stromal/stem cells. Biomaterials, vol.34(31): 7799–7810.

Wang S, Aurora A B, Johnson B A, et al., 2008, The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Developmental Cell, vol.15: 261–271.

Fish J E, Santoro M M, Morton S U, et al., 2008, miR-126 regulates angiogenic signaling and vascular integrity. Developmental Cell, vol.15(2): 272–284.

Szpalski C, Barbaro M, Sagebin F, et al., 2012, Bone tissue engineering: Current strategies and techniques—Part II: Cell types. Tissue Engineering Part B: Reviews, vol.18: 258–269.

Szpalski C, Wetterau M, Barr J, et al., 2011, Bone tissue engineering: Current strategies and techniques—Part I: Scaffolds. Tissue Engineering Part B: Reviews, vol.18: 246–257.

Karlsen T A, Jakobsen R B, Mikkelsen T S, et al., 2013, microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem Cells and Development, vol.23: 290–304.

Gurusinghe S and Strappe P, 2014, Gene modification of mesenchymal stem cells and articular chondrocytes to enhance chondrogenesis. BioMed Research International, 2014: 369528.

Peng W, Unutmaz D and Ozbolat I T, 2016, Bioprinting towards physiologically relevant tissue models for pharmaceutics, Trends in Biotechnology, vol.34: 722–732.

Ravnic D J, Leberfinger A N, Koduru S V, et al., 2017, Transplantation of bioprinted tissues and organs: Technical and clinical challenges and future perspectives. Annuals of Surgery, vol.266(1):48–58.

Heinonen M, Oila O and Nordström K, 2006, Current issues in the regulation of human tissue-engineering products in the European Union. Tissue Engineering, vol.11: 1905–1911.

Yanke A B and Chubinskaya S, 2015, The state of cartilage regeneration: Current and future technologies. Current Reviews in Musculoskeletal Medicines, vol.8: 1–8.

Yu Y, Moncal K K, Li J, et al., 2016, Three-dimensional bioprinting using self-assembling scalable scaffold-free “tissue strands” as a new bioink. Scientific Reports, vol.6: 28714.

Marco F, Lopez-Oliva F, Fedz-Arroyo J M F, et al., 1993, Osteochondral allografts for osteochondritis dissecans and osteonecrosis of the femoral condyles. International Orthopaedics, vol.17: 104–108.

Martín-Cartes J A, Tamayo-López M J and Bustos-Jiménez M, 2016, “Sandwich” technique in the treatment of large and complex incisional hernias. ANZ Journal of Surgery, vol.86: 343–347.

Peterson L, Minas T, Brittberg M, et al., 2003, Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation: Results at two to ten years. The Journal of Bone & Joint Surgery – American Volume, vol.85A(Suppl 2): 17–24.



  • There are currently no refbacks.

Copyright (c) 2017 Ibrahim T. Ozbolat

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.