Studies to date show the safety of using autologous human mesenchymal stem cells for bone regeneration in segmental long-bone defects. None of the reports mention adverse effects, such as inflammation or excessive tissue growth. In view of the report that extensively cultured mesenchymal stem cells (4-5 months) can develop genomic instability, an indicator of malignant transformation, the relatively short in vitro expansion period (6-8 weeks) may account for the lack of reported malignancy in the clinical studies performed so far.
The first clinical case report described three patients with various segmental long bone defects who underwent implantation of autologous mesenchymal stem cells. Macroporous 100% hydroxyapatite scaffolds, which were made to fit the shape and size of the defect, were loaded with ex vivo-expanded human mesenchymal stem cells isolated from their own bone marrow and implanted into the long-bone defects. After follow-up of 6-7 years, the implants were integrated into the bone with no further complications. Despite the lack of controls and no evaluation other than simple radiographs, this report demonstrated the safety of the procedure. In another report, one patient with a combination of autologous cancellous bone and stem cell-seeded porous calcium-triphosphate granules at ratio 1:2. Other clinical studies are case reports on reconstruction of maxillary or mandibular defect using various scaffolding materials, including fibrin glue, β-tricalcium phosphate or hydroxyapatite granules, and platelet-rich plasma.
Most reported human studies of stem cell-based bone regeneration are cohort outcome studies or case reports, because of the practical and ethical issues involved in conducting a randomised controlled trial. Published human clinical studies or case reports used autologous, culture-expanded, non-genetically modified human mesenchymal stem cells for bone regeneration. While the absence of controls is a major drawback, these preliminary cohort studies hint at the safety and potential therapeutic effects of autologous stem cell treatment.
To fascilitate regeneration of currently intractable large bone defects, stem cell therapy has emerged as a possible solution. Bone marrow injection, in a sense, represents a primitive form of stem cell therapy. The method had been used to treat long-bone defects and enhance fracture repair prior to establishment of the concept of stem cells. However, because various cells are present in bone marrow aspirate, a small proportion of which are stem cells, it cannot be truly categorised as a stem cell therapy.
To treat a large bone defect, harvesting a large portion of bone from other parts of the body inevitably creates significant morbidity at the donor site. Allografts from cadavers carry a risk of infection and disease transmission, as well as failure to incorporate into host bone if used in bulk. Bone substitute materials have limited osteogenic potential, and are not useful for complex bone reconstructions.
Stem cells for treating long-bone defects
Bone is one of the most frequently transplanted tissues. Unlike other tissues, complete regeneration occurs after bone injury, rather than healing with scar tissue. While most bone defects heal spontaneously or with autogenous bone grafting, critical size defects of long bone caused by major trauma or resection of malignant tumours pose a challenge in treatment.
Although musculoskeletal disorders are basically nonlethal, their high prevalence and relative ease of performing clinical trials have facilitated the clinical application of stem cells in this field. However, few reliable clinical studies have been published, despite the plethora of in vitro and preclinical studies in stem cell research for regenerative medicine in the musculoskeletal system. While randomised controlled clinical trials undoubtedly would produce the most reliable data, they are difficult to conduct because of high cost related to performing those studies. Therefore, most clinical data comes from case reports/cohort outcome studies which have problems in reproducibility and should be interpreted with caution.