Mesenchymal stromal cell products for intra-articular knee injections for conservative management of osteoarthritis

Abstract

Sports injuries and secondary joint problems, mainly of the knee, are common, especially in sports associated with high impact activities and/or torsional loading. The consequences can be career ending in elite athletes and reduce exercise activities in recreational people. Various cell products can be injected intra-articularly. First, fresh cellular mixtures can be prepared and injected in the same day, such as stromal vascular fraction of adipose tissue (SVF) and bone marrow concentrates (BMCs). Second, autologous mesenchymal stromal cells (MSCs) can be isolated from BMCs or SVF and, after several weeks of laboratory expansion, several millions of MSCs can be obtained for intra-articular injection. Finally, allogeneic MSCs from the bone marrow, adipose tissue or perinatal tissues of selected donors constitute an ‘off-the-shelf’ experimental treatment for injection delivery in patients with osteoarthritis of the knee. The perceived efficacy of all these products is based on the hypothesis of a paracrine mechanism of action: when living cells are delivered within the joint, they establish a molecular cross-talk with immune cells and local cell phenotypes, thereby modulating inflammation with subsequent modifications in the catabolic/degenerative milieu. Current clinical research examines whether injection delivery of MSCs translates into actual clinical benefits. Overall, clinical studies lack the quality needed to answer major research questions, including clinical and structural efficacy, optimal cell dose, and number of injections and specific protocol for cell delivery. Poor experimental designs are exacerbated by the diversity of patient phenotypes that hinder comparisons between treatments. Further understanding of disease pathology is paramount to develop potent function assays and understand whether the host tissue, the cell product or both should be primed before MSCs are injected intra-articularly.

Knee intra-articular administration of stromal vascular fraction obtained from adipose tissue: A systematic review

“…Garza et al 14 obtained better results in symptoms and pain with high-dose of intra-articular SVF and further studies are necessary to identify the optimal cell concentration and environment needed for clinical application of intra-articular injection in knee OA. 39,40 The area of fat harvesting and patient age may influence the stem cell yield, 41 but not all studies report the site of harvesting. The most important limit is that in many studies patients underwent concomitant procedures such as arthroscopic debridement, microfractures, or high tibial osteotomy, thus preventing a clear understanding of the real contribution and clinical potential of stem cell-based treatment.…”

“…Lipocell device Caforio 38 Lipocell device Adriani 39 Lipocell device Mautner 32 BMAC:Emcyte centrifuge. The MFAT: Lipogems® device Elnhal 33 Enzymatic digestion Bansal 25 Enzymatic digestion Lapuente 27 Enzymatic digestion Tran 29 Enzymatic digestion Koh 36 Enzymatic digestion Hong 12 Enzymatic digestion Roato 40 Centrifugation Pintat 28 Centrifugation Yokota 37 2017…”

Short-term results of intra-articular injections of stromal vascular fraction for early knee osteoarthritis

“…Hyaluronic acid (HA) injections are a repeatable option which may reduce pain, but HA does not reverse or repair the damaged cartilage [ 3 ]. Effectiveness of microfractures (MF), autologous chondrocyte implantation (ACI) or matrix-applied chondrocyte implantation (MACI), and autologous chondrocyte transplantation (ACT) in the management of OA is uncertain and unpredictable, suggesting benefits especially in the treatment of focal chondropathies [ 4 – 6 ]. In younger patients with medial compartmental osteoarthritis of the knee, valgus high tibial osteotomy reduces pain and improves knee function [ 7 ].…”

“…Bone marrow and adipose tissue are the main sources of MSCs: they can be harvested in a minimally invasive fashion and can be minimally manipulated intra-operatively with sterile devices [ 15 ]. In particular, adipose/fat tissue contains a greater concentration of MSCs than bone marrow (0.01–0.1% vs. 0.001–0.01%), it provides an abundant source of stromal vascular fraction (SVF) cells for immediate administration and, through enzymatic digestion, it can also give rise to a substantial number of multipotent adipose-derived stromal cells (ADSCs) [ 6 , 16 ]. These cells of the SVF have the potential to differentiate into adipogenic, osteogenic, chondrogenic, and other mesenchymal lineages [ 17 ].…”

Does vehicle-based delivery of mesenchymal stromal cells give superior results in knee osteoarthritis? Meta-analysis of randomized controlled trials

“…Various researchers have studied various methods of delivery of orthobiologics into knee joint (intra-articular, subchondral, intra-osseous, and biomaterial-based delivery) for regenerating the degenerated cartilaginous tissue in knee osteoarthritis (OA) most effectively. [3][4][5] Once administered, MSCs undergo radical biological and morphological changes and disappear from the site of injection within a few days of injection. 6 To regenerate cartilage, the environment needs a continuous release of biological peptides such as growth factors and cytokines to exert the paracrine signaling of MSCs to differentiate into chondrocytes.…”