Abstract
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Current non-surgical managements of osteoarthritis (OA) do not change the clinical course or arrest the progression of the disease, while joint replacement is indicated for end-stage disease. Given these limitations, there is an unmet clinical demand for new treatment modalities that can improve the pain and quality of life of patients suffering from OA without surgery. The recent surge of interest in regenerative medicine (RM) for OA is based on these circumstances.
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Unlike traditional medicine, RM products may be accompanied by many uncertainties and long-term consequences. Considering that OA directly affects quality of life rather than life and death, the ‘first do no harm’ principle is more important when applying RM technology to the disease.
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Presently, culture-expanded mesenchymal stromal cells (MSCs) and orthobiologics, including bone marrow aspirate concentrate, stromal vascular fraction from adipose tissue and platelet-rich plasma have been applied to patients in clinical trials.
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Results of randomized clinical trials using MSCs have demonstrated that structural improvement and reversal of the pathologic process in OA are not definitely shown, while symptomatic relief is apparent.
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Orthobiologics seem to have efficiency comparable to those of culture-expanded MSCs. With the advantage of avoiding the approval process from regulation agencies, orthobiologics might provide a less expensive and handier option to culture-expanded MSCs.
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High-quality data from a large number of patients and head-to-head comparisons of several RM products will be necessary to define the place of culture-expanded MSCs or orthobiologics for OA treatment and resolve the reimbursement issue.
Introduction
Regenerative medicine (RM) is an interdisciplinary field of medicine that focuses on biological repair, replacement or regeneration of injured or diseased tissues. According to Daar et al., RM is an ‘interdisciplinary field of research and clinical applications focused on repair, replacement or regeneration of cells, tissues or organs to restore impaired function resulting from any case’ (1, 2).
In a broad sense, RM comprises any medical endeavor to regenerate tissues, including small-molecule drugs, biological therapies, tissue-engineered devices or cell and gene therapy (3). Compared with traditional medicine, applying a product developed for RM to patients can be accompanied by greater uncertainties of long-term consequences, which have aroused ethical issues for clinical application. Using RM products in clinics may bring about complications that are not expected in conventional treatments. Given these differences from conventional medicine, traditional ethical standards established for conducting clinical research need reconsideration and adaptation for RM (4).
Considering that osteoarthritis (OA) directly affects quality of life rather than life and death, this ‘first do no harm’ principle is more important when applying RM technology to the disease. Potential serious adverse reactions, particularly an increased risk of carcinogenesis, should be assessed as the first priority. Long-term follow-up is particularly emphasized for individuals conducting clinical projects using cell-based products because of the possibility that these substances can persist in the body and potentially cause malignancy. It should be borne in mind that negligence and underreporting regarding negative outcomes can be especially costly and harmful when monitoring RM products (5).
Need for RM in OA
OA is a chronic disease manifested by joint pain and reduced mobility of affected patients, thereby lowering quality of life (6). Although OA is not a lethal disease by itself, it is nevertheless a serious disease that can exacerbate associated comorbidities, including cardiovascular and metabolic diseases. While OA pathology is generally summarized as the loss of joint cartilage and thickening of underlying subchondral bone, OA can be heterogeneous in clinical features and responses to different treatments. Unfortunately, current non-surgical managements for OA are essentially time-buying measures that neither change the clinical course nor arrest the progression of the disease. To find fundamental therapeutics for OA, several disease-modifying OA drugs (DMOADs) have been developed, with some of them undergoing clinical trials. However, none of them has yet brought clinical success demonstrated by both structural improvement and symptomatic relief. In advanced OA, surgical treatments, primarily joint replacement, are at present accepted as the standard treatment (7). While joint replacement may eventually deliver an impressive result for end-stage OA, not all patients are happy with surgical outcomes, with 20% of patients unsatisfied with their results. Joint replacement can also potentially bring about life-threatening complications, including pulmonary embolism and periprosthetic infection. For these reasons, many patients still prefer a non-surgical solution for OA if available. Therefore, there is an unmet clinical demand for new treatment modalities that can improve the pain and quality of life of patients suffering from OA without surgery, even at advanced stages. The recently increased interest in RM for OA is based on these circumstances (8).
Design of clinical studies on RM for osteoarthritis
Treatment target
It can be argued whether early- or advanced-stage OA patients should be preferred candidates for RM treatment: the former is based on grounds that RM can provide an efficient cure before irreversible damage occurs and the latter is based on a rationale that RM can be the last resort after all other available treatments have already been tried. In practice, it is mostly applied in Kellgren–Lawrence grade 2–3 patients who have clinically evident but not end-stage disease (for which joint replacement is indicated). In orthopedic disorders, including OA, structural damages as demonstrated by radiological changes are not always equal to patients’ clinical symptoms. To be considered as a disease-modifying regenerative treatment, both symptomatic improvement and evidence of tissue regeneration are necessary. Adequate basic science and preclinical research should be performed to establish the mode of action of an RM product before considering clinical application. Before RM interventions are brought to patients, careful pilot studies and randomized controlled trials (RCTs) are preferred to introduce evidence-based medicine as much as possible. Efforts should be made so that clinical studies on RM are flawless and properly designed (9).
The comparator in RM clinical trials for OA
In a clinical experiment to test the efficacy of a treatment method, randomization of treatment and control groups that allows an unbiased perspective of efficacy and safety is the favored method (10, 11). Given that an RCT provides the most reliable information on the ultimate value of a treatment, the control or comparators in RCTs can be designated as one of the three: i) standard conventional care, ii) placebo or iii) no intervention. Placebos are preferred to ensure validity of the clinical trial, particularly when clinical endpoints such as quality of life are assessed in the trial (12). By blinding, in which one gets a tested treatment or placebo, nonspecific effects such as placebo effects and reporting bias can be kept to a minimum (13). Particularly with RM trials, these confounding effects could be accentuated by excessive unjustified expectations on these ‘new’ technologies from both patients and investigators. When an RM intervention is a rather invasive one or when the trial is performed for patients with serious symptoms, conventional treatment is preferred as the control arm unless the intervention is an additive one to the main treatment.
Current status of RM in OA
Mesenchymal stromal/stem cells
Mesenchymal stromal/stem cells (MSCs) have been the most investigated RM products in translational studies or clinical applications for OA. While bone marrow-derived MSCs have been the mainstay sources, those isolated from fat or umbilical cord blood have also been tried as candidate sources because of their own merits. Anti-inflammatory and immunomodulatory properties of MSCs are known to provide joint environments better suited for the regeneration of damaged articular cartilage, either with transplanted MSCs or with endogenous cells mobilized by paracrine factors released from MSCs (14).
The original anticipation in cell therapy for cartilage regeneration was that implanted cells would survive, incorporate into chondral defects and differentiate to articular chondrocytes producing the extracellular matrix. Therefore, cell treatment would lead to structural improvement of the damaged joint by regenerating articular cartilage (15). However, it became obvious that intra-articularly (IA) administered cells survived only transiently and underwent rapid cell death (16). Most IA-administered MSCs survived from a few days to several weeks, depending on the mode of administration and the local environment (17, 18). Paracrine factors released from administered cells before undergoing apoptosis are thought to exert immunosuppressive and anti-inflammatory functions, as well as chondro-induction for host cells. Interestingly, stem cells survived longer when implanted focally rather than diffusely injected (19). Efforts to prolong cell survival and thereby exert extended paracrine effects and/or enhance engraftment with chondrogenic differentiation merit further inquiry and investigation.
Orthobiologics
Orthobiologics are biological substances known to promote repair/regeneration of musculoskeletal tissues. They are mostly autologous and comprise bone marrow aspirate concentrate (BMAC), stromal vascular fraction (SVF) from adipose tissue, platelet-rich plasma (PRP), platelet lysate, autologous conditioned serum or plasma, autologous protein solution and growth factor concentrates. Autologous BMAC, SVF and PRP have been used for OA treatment or cartilage regeneration, more frequently in private clinics than in academic centers. While the mode of action has not been thoroughly investigated as in MSCs, their regenerative effects can also be explained by paracrine factors secreted from cells (20, 21, 22, 23).
Because orthobiologics are categorized as minimally manipulated products, they do not undergo preliminary review by regulation agencies, which is the norm for the drug approval process and takes a long time and much cost in terms of human resources (24). Minimal regulation and increased availability of orthobiologics have led to aggressive marketing and overuse of these products in some countries. On the other hand, in the clinical setting, practitioners face scanty guiding information and the deficient evidence-based literature (25).
Exosomes or extracellular vesicles
The other new field in RM for OA is the use of exosomes or extracellular vesicles (eVs). They are lipid bilayer-limited particles that are naturally released from a cell and take part in cell-to-cell communication. Nucleic acids, proteins, metabolites, lipids and sometimes organelles from parent cells are contained in eVs. Given that the paracrine action of MSCs is principally attributed to secreted eVs, eVs isolated from MSCs can replace MSCs per se in RM for OA treatment. Being free from nuclear material, eVs can present unique advantages in passing through the regulatory process. On the other hand, very few translational studies, let alone clinical studies, have demonstrated the efficacy of eVs for OA treatment. In addition, isolating eVs in clinically meaningful doses is still a very costly procedure currently. However, advantages of eVs in passing the regulatory process and application will invigorate future research (26, 27).
Clinical results from RM products applied to treat OA
Culture-expanded MSCs
Sixteen peer-reviewed RCTs that used culture-expanded MSCs to treat OA were available from the literature search. Of them, nine studies investigated autologous MSCs while seven used allogeneic MSCs. Bone marrow-derived MSCs were used in seven RCTs (28, 29, 30, 31, 32, 33, 34, 35). Adipose tissue-derived MSCs were used in seven studies (36, 37, 38, 39, 40, 41, 42). Placenta tissues- or Wharton’s jelly-derived MSCs were used in two studies (43, 44). Fourteen studies showed clinical improvements compared with baseline values at the final follow-up. Thirteen trials found significantly better clinical results compared with control groups. Mean ages of treated patients ranged from 51 to 66 years, reflecting the age range with a high OA prevalence. In addition, the women (57%) were greater in number than the men (43%), owing to the higher OA prevalence in women (45). Cell doses differed widely from one study to another, ranging from 3.9 × 106 to 1.5 × 108 cells. Most studies showed that MSCs were effective at mid-to-high doses (>40 × 106 MSCs). There is not a clearly defined efficacious MSC dose range that reproducibly and consistently leads to better results compared to other doses (46).
Results of RCTs demonstrate that structural improvement and reversal of the pathologic process in OA are not definitely shown with IA-injected culture-expanded stem cells, while symptomatic relief improvement seems to be apparent. While long-term follow-up of patients is necessary to monitor ultimate effects of MSCs in OA treatment and detect unknown potential mechanisms, few studies have tracked patients beyond 1 year. While symptomatic relief is not sufficient to justify the high cost associated with RM treatments, including culture-expanded stem cells, definitive structural improvement that would last for years or decades and obviate or delay the need for joint arthroplasty is yet to be demonstrated for culture-expanded stem cell therapy (46).
BMAC
As BMAC can be harvested in outpatient settings without a culture process and does not need complex regulatory hurdles for application to the patient, it can provide an alternative to MSCs, provided that the therapeutic effect is comparable to that of MSCs. BMAC actually contains relatively few MSCs (only 0.001–0.01% of cellular contents) (47, 48). BMAC can be safely harvested from patients with few complications (49). Although several studies have investigated the use of BMAC in OA patients (50), evidence is insufficient to confirm its unequivocal efficacy. While no significant harm from BMAC application has been reported, its acceptance as a suitable therapy for knee OA is limited due to inadequate supporting data and variable results.
Two high-quality studies have demonstrated that a single IA injection of BMAC in platelet-poor plasma is not more effective than a saline placebo injection regarding function, MRI-based cartilage appearance or pain control (50, 51). On the contrary, another high-quality study showed that BMAC plus platelet product IA injection functionally outperformed exercise therapy, with all patients switching treatments within 3 months after the study began (52).
Several RCTs have compared BMAC injections with injections of other substances as comparators. Two studies concluded that both BMAC and hyaluronic acid (HA) improved pain and function at 1–2 years post-injection as compared with baseline, with BMAC achieving better results in pain scale than HA (53, 54). According to these articles, BMAC demonstrated comparable or slightly better results than HA for alleviating pain in particular, if not structural improvement (53, 54). One RCT that compared BMAC, HA and PRP reported clinical improvements with all three injectables, with BMAC showing superior results to the other two at a year after injection (55) while other RCT that compared BMAC and PRP found no difference between the two injectables after 2 years of follow-up (24). With the above findings, BMAC appears to exert similar effects on pain and function in OA patients as PRP does. However, whether BMAC is the orthobiologic superior to PRP remains unclear. Notably, a high-quality study that prospectively compared BMAC, PRP, HA and corticosteroid (CS) reported no differences in clinical parameters or significant changes in MRI findings after long-term follow-up over 1 year (56). These results suggest that strong placebo effects exist in injection therapy per se, raising questions about the long-term efficacy of BMAC.
In summary, BMAC injections do not show undisputedly superior results in pain relief or functional improvement compared to conventional therapies such as HA or CS, despite some studies reporting longer duration of effectiveness. The evidence of structural improvement, the original rationale of cell therapy, is also scarcely reported. In consideration of these findings, it is suggested that high-quality data from a large number of patients are needed to define the place of BMAC injection for OA treatment (7).
Stromal vascular fraction (SVF)
The SVF, a cellular mixture derived from lipoaspirate, can be obtained through mechanical or enzymatic separation (57, 58). The SVF comprises a diverse group of cells including adipose-derived MSCs (ADMSCs), also known as adipose stromal/stem cells (ASCs), preadipocytes, macrophages, lymphocytes, endothelial progenitors, fibroblasts, pericytes, smooth muscle cells and other uncharacterized cells, along with extracellular matrix (59, 60). The proportion of ASCs in the SVF may vary widely from less than 1% to more than 15%, depending on the donor’s age, sex, health status and the method utilized for harvesting it from adipose tissues (60). The SVF is particularly attractive due to its accessibility, low complication rate and minimal donor-site morbidity (60).
Compared to studies on BMAC, fewer randomized, prospective studies that offer unbiased information against placebo or other conventional treatment are available. The crucial advantage of the SVF over ASC is that it bypasses strict regulatory approval whereas its main disadvantage lies in its composition, which is a mixture of various cell types that can impede quality control. Consequently, allogeneic therapy with SVF is not recommended (61). Unlike BMAC, which requires only aspiration needle and centrifuge for processing, the production of the SVF requires a semi-laboratory facility to digest the tissue using enzyme treatment or a micro-fragmentation machine to mince the acquired fatty tissue. Subsequently, the SVF is less accessible to practicing clinicians compared to BMAC, even less so than PRP. Given this disadvantage, the value of the SVF will hinge on its competitive advantage in efficacy over other biologics.
Two controlled studies indicated that the SVF was superior to saline, which possesses a strong placebo effect merely from injection, in terms of pain and functional improvement. Compared to HA, the SVF demonstrates a more durable effect (62, 63). In addition, a few studies that utilized MRI in follow-up showed increased cartilage thickening with the SVF (64, 65, 66). On the other hand, a high-quality study demonstrated that none of the three orthobiologics – BMAC, SVF, PRP – outperformed corticosteroid injections in terms of functional improvement and MRI features (56). Two other studies comparing BMAC and SVF also found no differences in outcomes between the two orthobiologics (67, 68).
Injection volume, cell dose and product quality control are unsolved issues with the use of SVF for OA treatment. In addition, isolation processes, including collagenase digestion and mechanical dissociation, are not standardized and differ among studies. When compared to outcomes with culture-expanded ASCs, which also showed recognizable symptomatic improvement over a longer term than HA but failed to achieve significant structural improvement (38, 69, 70, 71, 72), the effects of SVF, which is a mixture of various cells, do not appear inferior. A study that compares SVF injection with ASC injection head-to-head may provide interesting data to resolve this issue.
Based on the limited literature available, it is suggested that SVF may offer better long-term symptomatic relief than placebo or HA, and its effects are comparable to those of BMAC. Prospective studies with improved control over cell isolation methods, dosing and patient selection are necessary to provide convincing evidence of SVF’s efficacy in treating OA.
PRP
PRP refers to plasma containing concentrated platelets. It is enriched in growth factors that can promote tissue repair, cellular growth and angiogenesis. It includes platelet-derived growth factor, transforming growth factor-beta and vascular endothelial growth factor (73). Like other orthobiologics, PRP has been considered as a disease-modifying therapeutic for OA due to its anti-inflammatory and tissue-regenerative potential (73). The process of obtaining PRP is simpler with less morbidity than the process of obtaining BMAC or SVF. PRP has been used in autologous base and associated with a low incidence of adverse effects (74, 75, 76).
Compared with BMAC and SVF, PRP has more published data on OA because it began to be applied earlier. Systematic reviews of randomized trials have shown a significant decrease in visual analog scale score for pain with improved functionality and quality of life following PRP treatment in knee OA patients (75, 76). On the other hand, PRP injection therapy did not significantly reduce pain symptoms in patients with hip OA. In addition, the analgesic effect of leukocyte-poor PRP was greater than that of leukocyte-rich PRP (75). While evidence remains mixed, PRP treatment was not associated with a significant increase in cartilage thickness (77). As with BMAC and SVF, the optimal dose and multiplicity of injection for PRP in knee OA remain debated. Inconsistencies remain on whether higher doses or repeated injections of PRP could enhance pain relief and improve functional results (74, 76).
Recent analysis of statistical fragility of RCTs assessing the use of PRP for treating knee OA reported that given statistical significance might be reversed with only a few changes in patient outcomes, meaning that the significance of results in these RCTs is not robust enough (78, 79). Of note, a large randomized, placebo-controlled clinical trial showed negative results of PRP. That study was performed for Kellgren and Lawrence grade 2 or 3 OA patients to evaluate effects of IA PRP injections on symptoms and joint structure with participant, injector and assessor blinded. IA injection of leukocyte-poor PRP compared to saline placebo injection did not result in a significant difference in symptoms or joint structure at 12 months (80). At present, on grounds of insufficient high-quality evidence about its efficacy for symptomatic and structural improvement, most clinical guidelines do not recommend PRP for knee OA. Guidelines emphasize the need for rigorous studies to justify the use of PRP over less expensive conventional treatments.
To sum up, though PRP shows promise, high-quality data that show unquestioned efficacy of PRP are insufficient and the variability in preparation methods, dosage and treatment protocols presents challenges in standardizing its clinical application. Future research should focus on RCTs that compare PRP in different formulations and combinations with established therapies to thoroughly evaluate its efficacy and establish guidelines.
Conclusion
As applying end products of RM development to patients can be accompanied by many uncertainties not seen in conventional medicine, long-term follow-up is important for individuals undergoing clinical trials using cell-based products. Before RM products are approved for clinical application to patients, careful pilot studies and RCTs are necessary to establish evidence-based medicine as much as possible.
Presently, culture-expanded MSCs and orthobiologics including BMAC, SVP and PRP have been applied to patients in clinical trials. Results of RCTs using culture-expanded MSCs have demonstrated that structural improvement and reversal of pathologic process in OA are not definitely shown while symptomatic relief seems to be apparent. Given that symptomatic relief is not sufficient to justify the high cost associated with culture-expanded stem cells, definitive structural improvement that could last for years/decades and obviate/delay the need for joint arthroplasty is yet to be demonstrated for culture-expanded MSCs therapy.
Orthobiologics may also offer better long-term symptomatic relief than control arms including HA, CS or placebo although a few high-quality studies have demonstrated no advantage over conventional treatments. Likewise, the evidence of structural improvement, the original rationale of cell therapy, is scarcely reported. Although direct head-to-head comparison is not available, efficacies of orthobiologics have been reported to be comparable to those of culture-expanded MSCs. With the advantage of avoiding the approval process from regulation agencies, orthobiologics might provide a less expensive and handier option to culture-expanded MSCs therapy. In consideration of these findings, it is suggested that high-quality data from a large number of patients and head-to-head comparison of several RM products will be necessary to define the place of culture-expanded MSCs or orthobiologics for OA treatment and resolve the reimbursement issue.
ICMJE Statement of Interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work.
Funding Statement
This work was supported by the research grant from the Korean Fund for RM (RS-2022-00070271).
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