The 6 studies included 300 knees (124 with OA and 176 with focal cartilage defects) (Table II). The mean age was 54.85 years (range, 34 to 56 years) for the patients with OA and 45 years (range, 24 to 54 years) for the patients with cartilage defects. The Kellgren-Lawrence (K-L) classification was reported in the OA studies. Only Wong et al. documented the defect size in the studies involving focal cartilage defects33. The mean follow-up duration was 21.02 months (range, 12 to 36 months).
The cell source, collection technique, cell processing, qualitative and quantitative characterization, and delivery method varied widely among the studies (Table III). Details of the tissue collection technique were absent from most reports. Five studies used autologous cells29-33 and 1 used allogeneic cells19. Three studies used freshly isolated tissue-derived nucleated cells, 2 used mixed adipose-derived nucleated cells (MADNCs)29,30, and 1 used mixed blood-derived nucleated cells (MBDNCs)32. Three studies used culture-expanded cells derived from bone marrow aspirate19,31,33 (CEACs; culture-expanded adherent cells). The cell dose varied from 1.2 to 40 million cells. Qualitative cell characterization of injected cells using surface markers was done in 5 studies19,29,31-33. Only Koh et al.29 assayed the cell population using a colony-forming unit (CFU) assay. Five studies performed 1 cellular therapy injection, supplemented this injection in 3 studies with subsequent doses of PRP or HA19,29-31,33. One study32 performed a series of 8 cellular therapy injections in the course of treatment.
In addition to cellular therapy, the studies varied widely with respect to adjuvant factors that were included: PRP29,30, high tibial osteotomy29,33, HA31-33, and microfracture31 (Table II).
Patient-Reported Outcome Measures
Primary outcome measures are summarized in Table IV. Significant improvement in patient-reported outcome measures in the cellular treatment groups were reported in 5 studies: Wong et al.33, Koh and Choi30, Koh et al.29, Vega et al.19, and Lee et al.31.
The use of imaging also varied widely (Table V). One study19 in the OA group and 3 in the cartilage defect group31-33 used MRI (magnetic resonance imaging) for follow-up assessment at 12 to 18 months. Each reported improvement in the treatment group. The Poor Cartilage Index (PCI)19, the MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) system34, and 2 previously unreported subjective systems for MRI assessment31,32 were used.
Second-look arthroscopy was used in 2 studies29,32. Koh et al.29 reported that partial or fibrocartilaginous coverage was achieved in 50% of the treatment group, but in only 10% of the patients in the PRP-only group (p < 0.001), at a mean of 20 months after treatment. Saw et al.32 included cartilage biopsy as well and reported an increase in the HA group on the basis of ICRS (International Cartilage Repair Society) II histological scores (p = 0.022).
Five of the 6 studies reported on adverse events19,30-33. There were no major adverse reactions. Among the OA studies, 24 minor events were reported; 23 were reported by Vega et al.19 and consisted of transient pain, effusion, or inflammation controlled with NSAIDs (nonsteroidal anti-inflammatory drugs). One cartilage defect study reported no complications31. Saw et al.32 reported 85 minor events, most commonly warmth and swelling followed by knee motion difficulty. There was no trend toward greater adverse events in the treatment compared with control groups.
Methodological Quality Assessment
The mean mCMS (and standard deviation) of the 6 studies was 59.1 ± 16 (range, 32 to 82) out of 100 (Table VI). The prospective studies achieved a mean mCMS of 65 (range, 50 to 82).
The common thread of the studies reporting intra-articular cellular therapy injections for the treatment of OA and focal cartilage defects in the knee was positive clinical outcomes and no major adverse events. However, the studies were highly heterogeneous and meta-analysis was not feasible. The outcome differences reported between the study and control groups are modest, and randomized but unblinded methodologies do not control for patient or clinician-related bias. As a result, no conclusion can be drawn that current methods of cellular therapy provide generalizable benefit to patients.
The fact that treatment effects were found to be only modest in nature does not diminish the potential value of cellular therapies, however. Treatments with the capacity to modify the intra-articular environment to reduce inflammation, preserve cartilage, or induce cartilage regeneration are of increasing interest because of the rising numbers of patients with diseased cartilage. Both the athletic and aging populations have a strong desire to remain active, enhance or preserve normal knee function, and avoid the expense and risk associated with knee arthroplasty.
As our understanding of the cell populations, biological processes, and environment needed for cartilage homeostasis and cartilage repair continues to grow, the use and outcomes of intra-articular cellular therapies require further investigation35. At present, these interventions have demonstrated only modest clinical improvements, and those findings could be impacted by a placebo effect.
The underlying premise is that the arthritic knee or areas of focal cartilage injury may be deficient in the content of a stem cell or progenitor cell population, and that this deficiency may be mitigated by the harvest and transplantation of cells. There are several possible mechanisms of action for transplanted cells. These mechanisms may theoretically include (1) homing of cells to sites of degenerative or missing cartilage, followed by proliferation and differentiation into functional cartilage or cartilage-like tissue, (2) repopulating of progenitor cell pools on the surface of the synovium or existing cartilage that may subsequently migrate into regions of cartilage damage or augment the ability of existing cartilage to resist degradation, and (3) repopulating of a cell pool that modifies the intra-articular milieu either through cell-cell interactions or through secretion of soluble factors to reduce inflammation and/or activate catabolic agents). These effects could be limited in duration if the transplanted cells survive only a short time in the knee. However, the effects could be long-lasting if the transplanted cells become durable residents in the knee, or if their action induces a durable change in the population of local cells and the intra-articular milieu. Injected cells could induce chemotaxis and migration of other deficient populations of autogenous cells, which may take up longer-term residence in the knee. Alternatively, the injection of cells might induce selective proliferation of local progenitors (i.e., auto-repopulation of otherwise dormant cell populations). To date, the presumed mechanism of action of the cellular therapies has been left largely unaddressed in the clinical literature, including the manuscripts evaluated in this study.
Several additional deficiencies need to be addressed in future investigations, if the field of cellular injection therapy for these and other conditions is to progress: (1) use of a standardized and objective system of nomenclature to describe the cell populations that are administered, (2) objective characterization of the harvest site and methods and of the quality of the starting cell population, (3) quantitative description of the processing methods used and of the effect of cell processing on the concentration and prevalence of the cell population(s) that are presumed to provide therapeutic benefit, (4) quantitative reporting on the composition of the injected cells (concentration, prevalence, and biological potential of various bioactive cell populations), (5) standardized use of patient-reported measures of pain and function before and after treatment, and (6) standardized use of imaging or other means of assessing the structural outcome of injection therapies with respect to cartilage preservation and restoration.
Standardized nomenclature is essential for clarity in scientific communication. Connective tissue progenitor (CTP) and mesenchymal stem cell (MSC) are terms that should be distinguished. CTPs have been defined as the heterogeneous group of stem cells and progenitor cells present in native tissues that can be activated to proliferate and generate progeny that differentiate into 1 or more connective tissue phenotypes (e.g., bone, cartilage, fibrous tissue, fat, muscle)36-40. CTPs are rare in native tissues, with a prevalence of between 1 in 2,000 and 1 in 40,000 cells, depending on the tissue. No specific set of markers identifies all CTPs; as a result, the concentration, prevalence, and biological potential of CTPs in a given cell population can only be estimated using in vitro CFU assays. Standardized criteria have recently been incorporated into an ASTM International standard for use with automated systems for image analysis41. CTP concentration, prevalence, and biological potential are valuable quality attributes reflecting the regenerative potential of cells that are harvested from tissues and cells that are processed by various means without in vitro culture expansion. These metrics should become standard features in future cellular therapy studies. Of the included studies, only the one by Koh et al.29 used a CFU assay.
When freshly isolated tissue-derived cells are used, and CTP prevalence and function are not measured on the basis of colony formation, it is most appropriate to define that population of cells as “mixed tissue-derived nucleated cells” (MTDNCs). This designation applies to the cells used in 3 of the 6 included studies29,30,32.
In distinct contrast to the term CTP, MSC was originally defined as denoting a population of purified, homogeneous, culture-expanded cells that retained the capacity to differentiate into multiple tissue types (bone, cartilage, and fat)42.
However, the term MSC has often been misused. The International Society for Cellular Therapy (ISCT) has helped to clarify this point by defining standard criteria that must be present in order to designate a cell population as MSCs: (1) culture-expanded cells that adhere to tissue culture plastic, (2) cells that retain the capability for trilineage differentiation (bone, cartilage, and adipose tissue), (3) cells expressing CD105, CD73, and CD90 (with 95% prevalence), and (4) cells lacking expression of CD45, CD34, CD14 or CD11b, CD79 alpha or CD19, and HLA-DR surface molecules43. If these criteria are not met, the term MSC should not be used. All 6 of the included studies used the term MSC to describe the active component of their cellular therapy, but only 1 of them used the term accurately. Although 2 studies used culture-expanded cells, only the cells studied by Vega et al.19 satisfied the ISCT criteria for MSCs.
The functional capacity of culture-expanded cell populations is also important, and may not correspond to surface marker expression44. As with CTPs, the proliferative capacity of culture-expanded cells and ability of these populations to differentiate into cartilage, bone, and fat under standardized culture conditions are valuable quantitative measures of potency. CFU assays are also appropriate for assessment of the biological potential of culture-expanded populations.
Cell Harvesting and Processing Methods
The cell source (peripheral blood, bone marrow aspirate [BMA], fat), anatomic location (buttocks, retropatellar fat pad), and methods of harvesting (excision, liposuction) and processing (digestion, density separation, in vitro expansion) are essential variables that require specific characterization to ensure reproducibility and systematic refinement in future work.
The technique for obtaining and subsequently processing BMA has a profound effect on the concentration and prevalence of CTPs in the aspirate sample45. Of the 3 studies that used BMA as the cell source, only the one by Vega et al.19 defined both the anatomic site and the technique. The 2 studies using adipose tissue29,30 both processed cells with enzymatic digestion and density separation with a centrifuge, but provided no data with respect to CTP yield or the biological performance of these processed cells.
Quantitative reporting of the composition of the injected cells requires characterization. This includes the number of nucleated cells, erythrocytes, and platelets, as well as the differential count of the nucleated cells. Estimates of CTP prevalence and biological performance based on CFU assays should be required for populations of freshly isolated cells. Characterization of cells with respect to cell surface markers (e.g., by flow cytometry) should be required for culture-expanded populations. Flow cytometry is not inappropriate for characterization of freshly isolated cell populations, but it has little value in estimating the prevalence of CTPs among these mixed cell populations. The heterogeneity of colony-founding CTPs with respect to CD markers and the very low initial prevalence of CTPs in the starting population of freshly isolated cells (often <1 in 10,000) leave CTPs undetectable by traditional flow cytometry.
Safety concerns are particularly important when considering cellular therapies, especially for non-life-threatening disorders. The risks involved in short-term processing are primarily the risk of compromised sterile technique or cell toxicity during processing. Culture expansion methods introduce the additional risk of inadvertent selection of clones with undesirable epigenetic or genetic changes46. This review did not reveal any safety concerns, particularly in the setting of autogenous cell transplantation. Only minor events were reported. This observation is comparable with previous reports of cell-based treatments in the orthopaedic literature47,48.
In conclusion, the efficacy of cellular therapy injections has not yet been established. The value and effective use of cell therapy in orthopaedics remain unclear largely because of the absence of (1) rigorous blinded clinical trials, (2) standardized use of nomenclature to define cell populations, and (3) quantitative metrics to define cell populations and clinical and structural outcomes49. Although many of the studies reported here were randomized, patients had not been blinded. Because cellular therapy carries a high level of expectation for possible benefits, it can constitute a strong source of bias in enrollment and in perception of patient-reported outcome50. Future clinical trials must overcome the abovementioned deficiencies50,51.
Investigation performed at the Cleveland Clinic, Cleveland, Ohio; The Steadman Clinic, Vail, Colorado; and the Italian Hospital of Buenos Aires, Buenos Aires, Argentina
Disclosure: No external funding was received for this study. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had a patent and/or copyright, planned, pending, or issued, broadly relevant to this work.
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