JSUR Journal

Figure 32: Male, 71 years, pre-intervention MRI.

Figure 33: Male of figure 32, two-month follow-up MRI: MSC only. only.

Figure 34: Female, 69 years, pre-intervention MRI.

Figure 35: Female of figure 34, two-month follow-up MRI: MSC

Figure 36: Female, 82 years, pre-intervention MRI.        

        

Figure 37: Female of figure 36, two-month follow-up MRI: MSC only.

 Figure 38: Male, 69 years, pre-intervention MRI.

Figure 39: Male of figure 38, two-month follow-up MRI: MSC only.

Figure 40: Male, 75 years, pre-intervention MRI.

Figure 41: Male of figure 40, two-month follow-up MRI: MSC only.

Discussion

The present study demonstrates that combining autologous Mesenchymal Stem Cells (MSCs) with an acellular type I collagen matrix (ChondroFiller^® liquid) can safely yield notable clinical improvements in patients with end-stage (Kellgren-Lawrence grade IV) Knee Osteoarthritis (OA), exceeding the benefits of MSC therapy alone. Our results show, that even in end-stage knee OA, clinical improvement is possible. Both treatment groups showed significant reductions in pain and disability over the course of two months, consistent with the known efficacy of intra-articular MSCs in advanced OA. In line with our findings, a recent phase II randomized trial of adipose-derived MSC injections in knee OA reported significant pain relief versus placebo, and a 2020 meta-analysis confirmed that MSC therapies provide meaningful improvements in pain and function beyond standard care [17, 18].

KOOS Subscores

Patients treated with MSC plus the ChondroFiller^® liquid (Group 2) showed consistently better functional recovery than those receiving MSC only (Group 1). All five KOOS subdomains (Pain, Symptoms, ADL, Sport/Rec, QOL) improved in both groups, but the combination therapy consistently outperformed the MSConly group, with statistically significant advantages in the Pain and Sport/Rec domains. Notably, the ability to perform sports or recreational activities improved by ~34 points (from 34.1/100 ± 3.12 to 68.15/100 ± 4.71) in Group 2 vs ~26 points (from 37.5 ± 4.5 to 63.5 ± 5.0) in Group 1. This difference suggests the acellular collagen scaffold facilitated a faster and more robust return to high-demand knee function. Patients who received the collagen matrix felt more capable of strenuous tasks (running, pivoting, etc.) than those with MSCs alone, indicating an early functional gain attributable to the acellular collagen scaffold’s presence. These findings align with emerging evidence that biomaterial scaffolds can enhance the efficacy of cell therapies by providing a supportive milieu for joint repair [11,19]. A recent systematic review of MSCladen hydrogels for cartilage regeneration found that incorporating a 3D matrix consistently improved outcomes in animal models and even in early clinical trials [19]. Similarly, one-step cartilage repair techniques in focal cartilage lesions – which combine bone marrow-derived cells with an acellular collagen scaffold in a single procedure – have demonstrated superior hyaline cartilage formation and clinical scores at follow-up [20]. By providing a physical framework for the cells, the scaffold appears to act as a regenerative niche, enhancing cell retention, engraftment, and subsequent tissue repair beyond what MSCs achieve on their own. In essence, the combination therapy leverages both the biologic power of MSCs and the structural support of the collagen matrix to more effectively restore joint function.

A key role of the acellular collagen scaffold is likely its contribution to structural regeneration and cartilage protection. The ChondroFiller^® liquid, composed of highly purified type I collagen, serves as a three-dimensional extracellular matrix mimic that fills cartilage defects or areas of degeneration. This scaffold can stabilize the MSC-rich concentrate at the target site and protect the reparative tissue from deleterious mechanical forces in the joint. In our study, the scaffold was injected intraarticularly, where it gelled within chondral defects and along damaged surfaces, forming a protective layer. Biomechanically, such a collagen gel may cushion impact and reduce shear stress on exposed subchondral bone or fragile repair tissue. A recent in vitro study confirmed that filling a cartilage defect with a collagen hydrogel can offload and preserve the opposing articular surface, whereas empty defects lead to greater wear of the intact cartilage [21]. In addition, the collagen matrix provides binding sites and a native-like architecture for cells to attach and organize. This ECM mimicry helps guide MSC differentiation towards chondrocytes and encourages the deposition of new cartilage matrix. Preclinical research has shown that MSCs embedded in collagen scaffolds exhibit enhanced chondrogenic differentiation and produce cartilage tissue of higher quality (with greater proteoglycan and type II collagen content) compared to MSCs delivered as a simple suspension [15,22]. In our context of diffuse osteoarthritic damage, the acellular collagen scaffold may have promoted a more homogeneous repair response, filling fissures and defects with a collagenous template that the MSCs (and perhaps endogenous progenitors) used to build new tissue. Although we did not obtain biopsy samples in this trial, the superior functional gains in Group 2 hint at improved structural repair. This is further supported by prior studies of collagen gel implants in joints – for instance, an arthroscopic study using ChondroFiller^® liquid in focal knee lesions demonstrated MRI evidence of defect filling and congruent joint surfaces at 1–5 year follow-up [14]. Taken together, these data suggest that the acellular collagen scaffold provided more than just a passive filler role: it actively enhanced the cartilage regenerative process, resulting in better joint integrity and function than MSC injection alone.

Pain Relief and Anti-Inflammatory Effects

Both treatment arms achieved a dramatic reduction in knee pain by 2 months, with VAS scores dropping from severe (8.54/10 ± 0.97) at baseline to mild (2.08/10 ± 0.76) after two months in Group 2. Group 1 also showed significant improvement with VAS scores decreasing from severe (8.34/10 ± 1.07) at baseline to mild (2.42/10 ± 0.90) after two months. Interestingly, pain relief was equivalent between Group 1 and Group 2 at this early time point. This indicates that the potent analgesic effect observed is largely attributable to the MSC therapy, which is consistent with the known paracrine action of MSCs in arthritic joints. MSCs can secrete anti-inflammatory cytokines, growth factors, and extracellular vesicles that modulate the intra-articular environment and alleviate pain [10]. Experimental OA studies have shown that the MSC secretome reduces synovitis and even diminishes pain behavior and cartilage damage in vivo [10]. In our patients, the injected MSC-rich concentrate (derived from peripheral blood) likely delivered a cocktail of immunomodulatory factors that rapidly calmed synovial inflammation and nociceptive signaling, explaining the swift drop in pain in both groups. The acellular collagen scaffold, on its own, would not be expected to provide such an early analgesic effect, since it does not actively secrete factors. However, it is encouraging that adding the scaffold did not diminish the pain relief – indicating that the biomaterial is highly biocompatible and does not provoke inflammation or immune reactions that could counteract the MSCs’ benefits. In our trial we observed no inflammatory flares or effusion attributable to the scaffold, corroborating its bio-inertness.

Over the short term, the acellular collagen scaffold’s contribution may be more structural and protective than analgesic, but it could have indirect pain benefits by stabilizing the joint (preventing mechanical irritation) and by facilitating tissue regeneration that addresses the root cause of pain. Additionally, collagen itself may exert some anti-inflammatory influence once polymerized in the joint. There is evidence that injected collagen can act as a biological response modifier; for example, intra-articular polymerized type I collagen has been shown in a randomized trial to downregulate inflammation in knee OA, leading to reduced pain, improved function, and decreased inflammatory mediators compared to placebo [23]. Collagen matrices can bind or sequester pro-inflammatory molecules and create a microenvironment that favors reparative over destructive processes [23]. Thus, while the primary pain relief in our study is likely due to the MSCs blunting synovitis, the acellular collagen scaffold probably complemented this effect by providing a calm, biofriendly niche rather than triggering any additional inflammation. It is conceivable that over a longer time frame, as the scaffold integrally participates in cartilage repair, patients in the combination group might maintain pain reduction better than those with MSCs alone (especially if the latter’s effect wanes once the injected cells die off). Our 2-month data, however, confirm that both treatments are very effective for short-term pain relief in end-stage OA, with the combination therapy matching the MSC therapy in analgesic efficacy while conferring extra functional benefits.

Imaging and Biochemical Findings

MRI evaluations in this study corroborated the clinical improvements and provided insight into the tissue-level effects of each therapy. Both groups demonstrated notable reductions in intra-articular pathology on MRI, including decreases in bone marrow edema (BME), synovitis, and joint effusion from baseline to 2 months. These MRI markers are important, as bone marrow lesions and synovial inflammation are associated with OA pain and progression. In Group 1, treated with MSCs, we observed a significant reduction in Bone Marrow Edema (BME), joint effusion, and synovitis over the 2-month followup period, consistent with the known anti-inflammatory and chondroprotective effects of cell-based therapy. At baseline, BME was present in 75% of patients (9/12), decreasing to 42% (5/12) at follow-up. Joint effusion was noted in 92% of patients (11/12) at baseline and declined to 58% (7/12) after two months. Synovitis was observed in all patients (100%, 12/12) at baseline and dropped to 58% (7/12) at follow-up. Group 2, treated with the combination of MSCs plus ChondroFiller^® liquid, exhibited even more pronounced improvements in all MRI parameters. BME prevalence declined from 69% (9/13) at baseline to 23% (3/13) at follow-up. Joint effusion was initially present in 92% of patients (12/13) and reduced to 31% (4/13) after two months. Likewise, synovitis decreased dramatically from 100% (13/13) at baseline to just 23% (3/13) at follow-up. Post-treatment MRI scans from this group frequently demonstrated reduced subchondral bone signal intensity, lower joint fluid levels, and diminished synovial inflammation compared to Group 1. Although our sample size is limited, this trend suggests that the addition of the acellular collagen scaffold may enhance the disease-modifying impact of the treatment by further normalizing the joint environment. A plausible explanation is that the scaffold, by promoting new cartilage-like tissue formation, reduces mechanical stress on the subchondral bone, thereby alleviating marrow edema.

The more robust fill of cartilage defects could also decrease exposure of bone and attenuate the inflammatory crosstalk between bone and synovium. In line with this, we found that MMP-13 levels in synovial fluid dropped in both groups over 2 months, but the reduction was significantly greater with the combined therapy. MMP-13 (matrix-metalloproteinase-13) is a key catabolic enzyme responsible for degrading type II collagen in articular cartilage and is considered a critical mediator of OA progression [24]. Elevated MMP-13 drives cartilage breakdown and is associated with pain and structural worsening in OA [24]. Therefore, the ability of a treatment to suppress MMP-13 is indicative of a protective or regenerative mechanism at the molecular level. In Group 1, MMP13 decreased by roughly 20% from baseline (from 127.78 ng/ml ± 13.15 at baseline to 102.51 ng/ml ± 13.23 after two months), reflecting the general anti-catabolic effect of MSC secretions (e.g., MSCs can release TIMPs and anti-inflammatory cytokines that downregulate MMP expression [23]. Notably, in Group 2, MMP-13 levels fell by nearly 40% (from 121.17 ng/ml ± 12.36 at baseline to 75.98 ng/ml ± 12.8 after two months), suggesting a more pronounced halting of cartilage breakdown. The acellular collagen scaffold may contribute to this by both biochemical and biomechanical means: it can serve as a temporary substitute for cartilage, taking on some load (thus lessening stimuli for MMP13 production), and it might also directly interact with cells to modulate their phenotype. Chondrocytes and synoviocytes in a stabilizing collagen-rich milieu could receive signals to decrease matrix-degrading enzymes. Indeed, other investigators have reported that applying a collagen-based gel to arthritic joints leads to reduced markers of cartilage degradation (such as urinary CTXII) in patients with knee osteoarthritis compared to controls [23]. The greater decline of MMP-13 in our combination group dovetails with the MRI finding of greater BME reduction: both point to an enhanced joint preservation effect when the acellular collagen scaffold is included. In sum, these imaging and molecular results support the idea that while MSC injections provide a potent antiinflammatory and symptom-relieving effect, the acellular collagen scaffold fortifies the treatment by fostering tissue regeneration and suppressing the underlying drivers of OA, like subchondral bone stress and enzymatic cartilage breakdown.

Range of Motion

Another encouraging outcome was the improvement in knee Range of Motion (ROM). At baseline, many patients had ROM deficits due to pain, swelling, and osteophytes common in grade IV OA. After treatment, both groups showed gains in ROM, with knee extension improving to a near-normal 0^° deficit on average. In Group 1, mean knee flexion increased from 115.4^° at baseline to 123.8^° at the two-month follow-up. In comparison, mean knee flexion improved from 120.4^° at baseline to 128.5^° at the twomonth follow-up in Group 2. Restoration of full extension is particularly important for gait and function, and this was achieved in both Group 1 and Group 2 patients. There was no significant between-group difference in ROM, likely because pain relief was comparable. The key point is that neither treatment caused any joint stiffness or other adverse effect that would limit motion; on the contrary, reducing pain and inflammation unlocked the knees to move more freely. The acellular collagen scaffold did not impede joint mobility – an important safety consideration given it solidifies inside the joint. Clinically, the ability to regain extension and maintain flexion range indicates improved functional capacity (reflected also in KOOS-ADL scores) and suggests that these biologic treatments can address not just pain but also stiffness and mechanical function in severe OA.

Comparison with Other Regenerative Strategies

 Our findings extend the growing body of literature on orthobiologic interventions for knee OA. Past studies have primarily focused on MSCs or platelet-rich plasma alone, reporting modest to substantial short-term benefits in pain and function. For instance, in addition to the adipose MSC trials noted above, allogeneic bone marrow MSCs have shown improvements in WOMAC scores over placebo [25], and various uncontrolled series have reported pain relief with autologous MSC injections at 6–12 months [26]. However, regeneration of cartilage in advanced OA using cells alone remains challenging, partly due to the hostile degenerative environment and cell loss after injection. The concept of augmenting cell therapies with scaffolds is rooted in tissue engineering principles and has been explored mostly in focal cartilage repair scenarios. One notable parallel is the matrix-assisted chondrocyte implantation (MACI) technique, where autologous cultured chondrocytes are seeded onto a collagen membrane and implanted into focal defects – this approach yields superior cartilage quality than injection of cells alone because the matrix keeps cells localized and supports their phenotype [27,28]. By analogy, our injectable collagen gel (ChondroFiller^® liquid) plays a similar role for MSCs delivered into an arthritic joint. There is sparse literature directly examining MSC + acellular collagen scaffold versus MSC alone in osteoarthritic human joints, making our study relatively novel. Nevertheless, evidence from related strategies is supportive. Gobbi et al. reported that a one-step procedure using bone marrow aspirate concentrate (which contains MSCs) embedded in a collagen matrix led to hyaline-like cartilage repair in full-thickness knee lesions and excellent clinical outcomes at 2 years [20]. In a randomized comparison of microfracture (which relies on bone marrow stem cells and a fibrin clot scaffold) versus a collagen gel implant for chronic cartilage defects, the collagen scaffold was found to be as effective as microfracture in improving function and MRI appearance of the repair tissue [29].

Limitations

This study represents the first prospective clinical investigation evaluating the combined use of autologous mesenchymal stem cells (MSCs) and an acellular collagen scaffold (ChondroFiller^® liquid) specifically in patients with Kellgren–Lawrence grade IV knee osteoarthritis. As a proof-of-concept trial, it provides valuable early evidence that joint preservation is achievable even in end-stage disease. Nevertheless, certain limitations must be acknowledged. First, the relatively small sample size (n = 25) and short follow-up period (2 months) limit the generalizability of our findings and preclude definitive conclusions regarding long-term structural outcomes. However, the consistency of improvements across multiple outcome domains, including KOOS, VAS, ROM, MRI, and MMP-13, strengthens the internal validity of the results and supports the biological plausibility of the observed effects. Second, the absence of a placebo or sham control arm restricts interpretation of treatment efficacy relative to natural history. Yet, the magnitude of improvement-particularly the dramatic VAS and KOOS changes-exceeds what is typically observed in placebo-controlled OA trials, and both groups received an active biologic intervention rather than standard care. Third, the nonrandomized design and lack of blinding may introduce potential bias. Future studies should therefore aim to include evaluator blinding and, if feasible, random allocation to reduce selection and performance effects. In sum, while these limitations warrant cautious interpretation, they do not diminish the clinical and mechanistic significance of the observed outcomes. This study lays the groundwork for future randomized, controlled trials and provides a compelling rationale to further explore MSC– scaffold combinations as a joint-preserving option in late-stage osteoarthritis.

Clinical Implications

For patients with advanced knee osteoarthritis who are poor candidates for surgery or seeking to delay TKA, the outcomes of this study offer a potential alternative. The combined MSC + acellular collagen scaffold therapy was delivered via intra-articular injection, an outpatient procedure with minimal downtime, and resulted in significant pain relief and functional gains by two months. Importantly, it did so without serious adverse events or inflammation, signaling a favorable risk-benefit profile. If such improvements can be sustained longer-term, this approach could bridge the treatment gap for end-stage OA patients who have exhausted conservative measures but are hesitant or highrisk for joint replacement. Our findings suggest that even when radiographic OA is severe, the joint retains some capacity for repair that can be unlocked with the right combination of therapies. The acellular collagen scaffold in particular may help stabilize the disease by reinforcing cartilage structure and mitigating further degeneration. There is evidence that collagen-based injectables can extend the time to knee replacement – one long-term observational study reported that repeated intra-articular polymerized collagen injections delayed the need for TKA by a median of about 5 years in patients with symptomatic knee OA [30]. While our trial was short, it sets the stage for exploring whether a one-time MSC + acellular collagen scaffold treatment (or a series of injections) can defer the “endpoint” of arthroplasty in a similar manner. Moreover, the improvements in high-level activities (KOOS Sport/Rec) seen with the combined therapy raise the possibility that certain patients could return to recreational exercise or physical jobs that would have been untenable with their previous pain and stiffness. From a healthcare system perspective, effective regenerative injections could reduce the burden of surgeries and associated costs if they enable patients to cope with their native joints longer.

Future Directions

The positive outcomes of this preliminary study justify further research on MSC + acellular collagen scaffold combination therapy in osteoarthritis. Longer-term trials are a top priority. A followup duration of at least 1–5 years is needed to determine if the structural benefits (as suggested by MRI and MMP-13 reduction) translate into slowed disease progression. Future studies should incorporate advanced imaging modalities such as quantitative MRI to objectively assess cartilage regeneration. Imaging at serial time points can track whether new cartilage matrix is forming and being maintained in areas treated with the acellular collagen scaffold. Larger randomized controlled trials with adequate power should be conducted to confirm these findings.

Conclusion

In conclusion, the integration of an acellular collagen scaffold with MSC therapy represents a promising frontier in OA treatment. Ongoing and future studies will determine if this combined regenerative approach can fulfill its potential as a joint-preserving, disease-modifying therapy for the millions suffering from advanced knee osteoarthritis. The groundwork laid by this trial provides a strong impetus for these next steps. While our early outcomes are encouraging, further research is warranted to confirm these benefits in larger patient populations and to determine the longevity of the repair. Future randomized trials with extended follow-up and detailed imaging evaluations will help establish whether this approach can achieve sustained cartilage regeneration and alter the long-term trajectory of knee osteoarthritis. If validated, such therapy could shift the paradigm of OA management toward less invasive, tissue-preserving interventions and offer patients an alternative path to pain relief and joint restoration short of artificial joint replacement.

Ethical Considerations

All participants provided written informed consent prior to enrollment. As a non-interventional observational study, the treatments were administered based on clinical decisions made independently of the study protocol.

Conflict of Interest

The study was financially supported by Meidrix Biomedicals GmbH. The sponsor had no role in the study design, data collection, data analysis, interpretation of results, or manuscript preparation. The authors declare that there are no other conflicts of interest relevant to this work

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