Application of Stem Cell Therapy for ACL Graft Regeneration

Abstract

Graft regeneration after anterior cruciate ligament (ACL) reconstruction surgery is a complex three-stage process, which usually takes a long duration and often results in fibrous scar tissue formation that exerts a detrimental impact on the patients' prognosis. Hence, as a regeneration technique, stem cell transplantation has attracted increasing attention. Several different stem cell types have been utilized in animal experiments, and almost all of these have shown good capacity in improving tendon-bone regeneration. Various differentiation inducers have been widely applied together with stem cells to enhance specific lineage differentiation, such as recombinant gene transfection, growth factors, and biomaterials. Among the various different types of stem cells, bone marrow-derived mesenchymal stem cells (BMSCs) have been investigated the most, while ligament stem progenitor cells (LDSCs) have demonstrated the best potential in generating tendon/ligament lineage cells. In the clinic, 4 relevant completed trials have been reported, but only one trial with BMSCs showed improved outcomes, while 5 relevant trials are still in progress. This review describes the process of ACL graft regeneration after implantation and summarizes the current application of stem cells from bench to bedside, as well as discusses future perspectives in this field.

Figure 1

Schematic model for graft regeneration after ACL reconstruction. (a) Early stage characterized by necrosis, fiber disintegration, and cytokine release; neutrophils, macrophagocytes, and mesenchymal stem cells (MSC) can be observed in the interface in order, and then macrophagocytes and MSC migrate into the inner tendon. The collagen fibers displayed a bimodal distribution, with large ones constituting the majority; (b) remodeling stage marked with Sharpey fibers (arrow), cell migration, vascularization, ECM remodeling, various growth factor activities, and disordered organization of collagen fibers (bimodal distribution with small ones constituting the majority); (c) ligamentization stage marked with vascularization gradually disappearing, fibrocartilage formation, and ordered collagen with almost unimodal small fibers; (d) normal ACL, 4-layer direct insertion including ligament, fibrocartilage, mineralized fibrocartilage, and bone in order. The collagen fibers showed unclear bimodal distribution.

Figure 2

Features of included animal studies. (a) Cell resources; (b) augmentations; (c) animal models; (d) general study outcomes. BMSC: bone marrow-derived mesenchymal stem cells; ADSC: adipose-derived stem cells; hUCB-MSC: human umbilical cord blood-derived mesenchymal stem cells; TDSC: tendon-derived stem cells; LDSC: ligament-derived stem cells.

Figure 3

The number of ongoing and completed clinical projects with positive or negative results in the application of different stem cell lineages after ACL reconstruction. BMSC: bone marrow-derived mesenchymal stem cells; MPC: mesenchymal precursor cell; ADSC: adipose tissue-derived stem cell; hCDB-MSC: human cord blood-derived mesenchymal stem cell.