Human Stem Cell Based Tissue Engineering for In Vivo Cartilage Repair: A Systematic Review

Abstract

Pure chondral defects represent the most clinically significant articular cartilage injuries. To inform the development of clinically suitable tissue-engineering strategies for chondral repair using cells from a human patient, the combination of human stem cells (HSCs), biomaterial scaffolds, and growth factors has been widely harnessed in preclinical animal models. Due to the large heterogeneity in study designs and outcome reporting in such studies, we aimed to systematically review literature pertaining to HSC based tissue engineering strategies in animal models of chondral repair such that trends may be identified and the utility of HSCs in chondral repair can be elucidated. An extensive search strategy was carried out through PubMed, MEDLINE, and EMBASE databases to identify relevant studies. Initially the title and abstract of 787 studies were screened after which inclusion and exclusion criteria sorted 56 studies for full-text evaluation. Following full text review, a final number of 22 articles were included. Out of 22 included studies, 16 used scaffold implantation, 2 used cell pellet implantation, and 4 used intra-articular injection to administer HSCs to the region of chondral defects. HSC-containing implants outperformed scaffold-only or untreated control groups in both large and small animals for chondral regeneration. Umbilical cord mesenchymal stem cells and hyaluronic acid-containing scaffolds emerged as popular stem cell and scaffold choices, respectively. However, the short analysis timepoints post cell implantation was a key limitation in many studies. This review highlights the versatility of HSCs in achieving chondral regeneration in vivo and the enhancement of chondral repair through the selection of appropriate three-dimensional scaffolds and growth factors which are essential to support cell growth, attachment, migration, and extracellular matrix synthesis. Considerable heterogeneity exists in outcome reporting, and only one article reported biomechanical evaluation of neocartilage. Standardized outcome reporting systems that include comprehensive biomechanical testing protocols should be utilized in future in vivo studies of cartilage tissue engineering as the biomechanical quality of neocartilage is of great functional significance.

Impact statement

The vast majority of articular cartilage defects is partial or full thickness in depth and do not extend into bone marrow unlike osteochondral defects, in which bone marrow-derived stem cells are naturally recruited. No such reparative response occurs in pure chondral defects, making them difficult to repair. Tissue engineering is a promising strategy toward achieving the goal of using human stem cells (HSCs) to repair chondral defects in patients. This review systematically evaluates and summarizes existing literature in which the utility of HSCs has been diversely investigated in animal models of chondral repair in vivo. In doing so, the review explores the stem cells, growth factors, and scaffolds harnessed in HSC-mediated cartilage repair and sheds light on opportunities for novel preclinical investigations.