Concise review: the clinical application of mesenchymal stem cells for musculoskeletal regeneration: current status and perspectives

Abstract

Regenerative therapies in the musculoskeletal system are based on the suitable application of cells, biomaterials, and/or factors. For an effective approach, numerous aspects have to be taken into consideration, including age, disease, target tissue, and several environmental factors. Significant research efforts have been undertaken in the last decade to develop specific cell-based therapies, and in particular adult multipotent mesenchymal stem cells hold great promise for such regenerative strategies. Clinical translation of such therapies, however, remains a work in progress. In the clinical arena, autologous cells have been harvested, processed, and readministered according to protocols distinct for the target application. As outlined in this review, such applications range from simple single-step approaches, such as direct injection of unprocessed or concentrated blood or bone marrow aspirates, to fabrication of engineered constructs by seeding of natural or synthetic scaffolds with cells, which were released from autologous tissues and propagated under good manufacturing practice conditions (for example, autologous chondrocyte implantation). However, only relatively few of these cell-based approaches have entered the clinic, and none of these treatments has become a "standard of care" treatment for an orthopaedic disease to date. The multifaceted reasons for the current status from the medical, research, and regulatory perspectives are discussed here. In summary, this review presents the scientific background, current state, and implications of clinical mesenchymal stem cell application in the musculoskeletal system and provides perspectives for future developments.

Figure 1.

Schematic illustration of cell delivery for musculoskeletal regeneration. Cell delivery can be facilitated in various fashions for the purpose of musculoskeletal regeneration. First, the cells can be retrieved from the human body and readministered without further modification, such as injection of autologous blood or bone marrow. Although marrow suspensions are thought to contain a higher percentage of stromal cells than peripheral blood, both represent crude mixtures with overall low abundance of mesenchymal stem cells (MSCs). MSC density can be increased by centrifugation of whole blood or marrow or recovery from cell filters, clotting, or other concentration methods. These methods are relatively simple, making them appealing for single-step usage procedures in the operating room, and, therefore, are not associated with high regulative hurdles. However, blood and marrow concentrates or coagulates still have to be considered very crude and undefined mixtures. Alternatively, cells and in particular MSCs can be harvested from blood, bone marrow, and tissues by digestion and adherent culture. Such cell populations are usually maintained in tissue culture for amplification under controlled good medical practice conditions with usually autologous serum. This method offers the opportunity for close monitoring of the cells under safety and quality aspects, as well as further cell selection. However, this approach presents the highest regulatory levels, in the context of specific requirements of each country and continent (European Medicines Agency and U.S. Food and Drug Administration). The use of unprocessed as well as ex vivo processed cells might be enhanced and supplemented by the use of a biomaterial scaffold, soluble factor, nucleic acid, or mechanical stimulation. Additional specific regulatory requirements must be met for the use of each of these supplements, as well as for their combined usage, indicating the complexity for such approaches from a biological, medical, and regulatory perspective.

Figure 2.

Example of clinical mesenchymal stromal cell delivery following ex vivo expansion for the treatment of avascular necrosis of the femoral head. (A): Autologous bone marrow aspiration from the posterior iliac crest. (B): For delivery, β-tricalcium phosphate (β-TCP) granules (black arrow) were soaked with an autologous stromal cell suspension and immersed in autologous fibrin (white arrow) to facilitate subsequent handling. (C): Adhesive stromal cell/β-TCP constructs were delivered to the bony defects via tubings that were placed into the canals of the core decompression. (D): Postoperative radiography displays a 10-mm drill hole 6 weeks after core decompression completely filled with the stromal cell/β-TCP construct in a 34-year-old male patient with avascular necrosis (stage ARCO II) of the femoral head.