Within or Without You? A Perspective Comparing In Situ and Ex Situ Tissue Engineering Strategies for Articular Cartilage Repair

Abstract

Human articular cartilage has a poor ability to self-repair, meaning small injuries often lead to osteoarthritis, a painful and debilitating condition which is a major contributor to the global burden of disease. Existing clinical strategies generally do not regenerate hyaline type cartilage, motivating research toward tissue engineering solutions. Prospective cartilage tissue engineering therapies can be placed into two broad categories: i) Ex situ strategies, where cartilage tissue constructs are engineered in the lab prior to implantation and ii) in situ strategies, where cells and/or a bioscaffold are delivered to the defect site to stimulate chondral repair directly. While commonalities exist between these two approaches, the core point of distinction-whether chondrogenesis primarily occurs "within" or "without" (outside) the body-can dictate many aspects of the treatment. This difference influences decisions around cell selection, the biomaterials formulation and the surgical implantation procedure, the processes of tissue integration and maturation, as well as, the prospects for regulatory clearance and clinical translation. Here, ex situ and in situ cartilage engineering strategies are compared: Highlighting their respective challenges, opportunities, and prospects on their translational pathways toward long term human cartilage repair.

Keywords: 3D bioprinting; biomaterials; cartilage tissue engineering; in situ tissue engineering; stem cells.

Figure 1

An illustration of the main processes required for each prospective tissue engineering strategy. One key difference is where maturation of the tissue construct takes place: Occurring prior to implantation in the case of the ex situ fabrication strategy, but after implantation in the case of the in situ approach. The repercussions of this central difference are felt up and down the process chain, influencing every other aspect of the intervention.

Figure 2

A comparison of the ex situ and in situ cartilage engineering strategies. On the left‐hand‐side we consider an archetypal ex situ cartilage engineering strategy where a cartilage tissue construct is pre‐fabricated and matured in the lab prior to implantation. The pre‐fabricated construct can approximate the stiffness of natural cartilage, however the construct does not exactly match the shape of the debrided chondral defect. Interfacial discontinuities interrupt communication between native and implanted cells, and the infiltration of synovial fluid may negatively impact integration. On the right‐hand‐side we consider an archetypal in situ cartilage engineering strategy where a bioscaffold milieu (hydrogel + mesenchymal stem cells) is delivered arthroscopically to fill the defect site, and the crosslinked in place. The integration of the bioscaffold is an active process as MSCs release stromal factors with anti‐inflammatory and trophic effects upon the host tissue. Growth factor delivery systems as well as exogenous factors contribute to differentiation of MSCs toward the chondrocyte lineage and produce new ECM, which integrates with the ECM of the native tissue. The bioscaffold is initially softer than the surrounding cartilage, but stiffness increases as ECM is released during chondrogenesis.