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Review: Engineering Articular Cartilage Through Bioassembly

Key findings

  • Most conventional methods for engineering articular cartilage tissue are "top-down" approaches: seeding chondrocytes or stem cells in a bulk-sized scaffold or matrix that has the same or similar dimensions as the targeted tissue
  • The contrasting "bottom-up" approach, also known as bioassembly, involves combining scaffold-free cellular spheroids, or cell-containing polymer or hydrogel microspheres, to construct a microtissue
  • Advantages of bioassembly over top-down approaches include lower cost, the ability to approximate native tissue more closely, and greater ease of creating multicellular structures and complex tissue features
  • The two categories of bioassembly are manual (simple pipetting or assembly in an anatomically shaped model) and 3D bioprinting
  • One challenge of bioassembly researchers are exploring is how to produce microcartilage that has more native characteristics and can be better integrated into host cartilage

Articular cartilage defects are highly prevalent—they can result from trauma, osteoarthritis, osteochondrosis dissecans, osteonecrosis, and chronic polyarthritis. Cartilage regeneration was one of the earliest research emphases when the field of tissue engineering was launched in the 1970s.

Most conventional methods for engineering articular cartilage tissue are "top-down" approaches. Typically, chondrocytes or stem cells are seeded in a bulk-sized scaffold or matrix with the same or similar dimensions as the targeted tissue.

The contrasting "bottom-up" approach is also known as bioassembly—combining microtissues or micro-precursor tissues to construct a macrotissue. The minimum fabrication units are preformed cell-containing materials that are large enough to permit automated assembly.

Brian E. Grottkau, MD, director of the Laboratory for Therapeutic 3D Bioprinting in the Department of Orthopaedics at Massachusetts General Hospital, and Zhixin Hui, MS, and Yonggang Pang, MD, PhD, researchers in the lab, recently reviewed bioassembly of articular cartilage tissue in Cells.

Advantages of Bioassembly

Bioassembly has several advantages over top-down tissue engineering:

  • Size—The difficulty of immobilizing live cells in macroscale scaffolds can result in low cell densities and heterogeneous spatial cell distributions that don't match the corresponding native tissue. Bioassembly isn't associated with these problems because the materials are sub-millimeter in size
  • Complexity—Scaffold-based approaches complicate generating multicellular structures or complex tissue features such as repeated features or structures, tissue junctions, and structural zones. In contrast, micro–building blocks can be generated individually for different tissue types and be spatially assembled afterward
  • Replication—Top-down engineering generally fails to mimic the unit-repetitive modular patterns in native human tissues, such as nephrons, lobules, and islets. Bioassembly makes it easier to generate numerous replicates of building blocks to create repetitive units
  • Cost—In scaled-up production, bioassembly is usually less expensive than top-down approaches

Spherical Building Block Manufacture

The authors focus the review on spherical microcartilage building blocks that contain live chondrogenic cells, including chondrocytes and mesenchymal stem cells:

  • Scaffold-free cellular spheroids
  • Cell-laden polymer microspheres
  • Cell-laden hydrogel microspheres

Figures in the article show numerous methods for generating these materials.

Techniques for Bioassembly

The two categories of bioassembly methods are:

  • Manual assembly—Simple pipetting or assembly in an anatomically shaped model
  • 3D bioprinting—Extrusion or aspiration bioprinting, assembly using spherical building blocks and polymer hybrid bioprinting, or needle array–based spheroid bioassembly

Persistent Problems

The simplicity of cartilage is the reason it's so hard to recreate. Despite decades of research, two critical problems remain:

  • Loss of native phenotype—Chondrocytes in engineered tissue tend to change into fibroblast-like cells. In scaffold-free cellular spheroids and cell-laden hydrogel microspheres, chondrocytes change to fibroblastic type when packed closely. In cell-laden polymer microspheres, cartilage-like tissue can be seen in vivo only in some areas of the assembled macrotissue after the polymers degrade and neotissues are remodeled
  • Poor integration—Microcartilage building blocks are difficult to integrate completely into host cartilage. Cellular spheroids can fuse only into small and thin circular diameters (>5 mm), boundaries of individual modules remain, necrotic cores form, and the mechanical properties of fused tissues are poor

Future Directions for the Technology

In bioassembled cartilage, chondrocytes are usually homogeneously packed (cellular spheroids) or nearly evenly distributed (polymer or hydrogel microspheres). In contrast, cells in native cartilage usually distribute themselves into characteristic patterns that persist for the lifetime of healthy cartilage. There's some evidence these patterns serve as biophysical signals to control cell phenotype and functions.

Future studies may determine how to arrange chondrocytes into these patterns inside individual bioengineered building blocks. That may help the building blocks grow into microcartilage that has more native characteristics and integrates better into host cartilage.

Learn more about the Laboratory for Therapeutic 3D Bioprinting

Learn more about Research Opportunities in the Department of Orthopaedic Surgery


Massachusetts General Hospital researchers are using a novel approach—direct-volumetric drop-on-demand (DVDOD) technology—to three-dimensional (3D) bioprint healthy articular cartilage.


In this video, Brian E. Grottkau, MD, chief of the Pediatric Orthopaedic Service and director of the Lab for Therapeutic 3D Bioprinting at Massachusetts General Hospital, discusses some of the research projects currently underway at the lab.