**6.3 Not every bone marrow concentrate is born equal**

Currently, eight BMC harvesting devices are available on the market, producing different formulations of BMC and tissue viabilities and yielding different cellular concentration characteristics [111, 112]. As such, BMC preparations may vary widely regarding HSCs, MSCs, progenitors, platelet growth factors, and RBC content. Given this heterogeneity, the impact of BMC therapies on tissue regeneration may vary greatly. Explicitly, it is important to understand that the BMC

**25**

*The Rationale of Autologously Prepared Bone Marrow Aspirate Concentrate for use…*

ing signaling relationships is not completely understood [114].

validation processes and elucidating on potential dose responses.

non-stem cell cellular components in the treatment vial might have significant roles regarding behavior and function of MSCs. Recently, the cellular variances were confirmed in a systematic review, evaluating BMC studies in musculoskeletal pathologies [53]. Presumably, as postulated by numerous authors, the variances in BMC cellular compositions have a significant effect on the biological activity and regenerative potency of the treatment specimen, and these inconsistencies impact clinical outcomes [111, 113]. Unfortunately, an exact understanding of the underly-

**7. Bone marrow-derived mesenchymal cells in musculoskeletal disorders**

The use of autologous BM-derived MSCs for the treatment of a variety of musculoskeletal ailments is progressing significantly. Literature findings demonstrate positive outcomes after regenerative medicine MSC applications, in particular in joints, tendons, and bone, and hold great promise for future MSK-D applications, especially if more research and larger clinical trials are performed, focusing on cell

In this section we will present several clinical studies in which autologous, heterogenous BMC was used as a regenerative biologic to treat a variety of musculoskeletal disorders [42, 115]. Studies reporting on similar pathologies using BM-derived/ cultured MSCs are not mentioned as it has been reported that these technologies have different biomedical properties and extraction methods [116] and potentially possess new challenges and indications, when compared to at POC prepared fresh autologous BMCs. In clinical settings, BMC has been exploited as an ortho-biological treatment option for a range of indications, like symptomatic focal femoral head osteonecrosis, OA of the knee and hip, focal chondral defects, as well as another MSK-D. The rationale to use autologous BMC in osteoarthritic (OA) joints and other indications is its potential in facilitating anti-inflammatory and anabolic effects after injection. Moreover, the heterogenous BMC cellular assortment is known for its angiogenetic properties, therefore contributing to chondrocyte metabolism and inducing homing of (progenitor) stem cells to the treated areas [117]. Rodriguez-Fotan and co-workers used a two-step BMC preparation protocol in patients with early onset of OA in the knee or hip (Kellgren-Lawrence grades I–II, Tönnis grades I–II, respectively), with BMA aspirated from the anterior iliac crest. After a single BMC injection, 63% of treated patients had improved clinical symptoms at 6-month postinjection. They concluded that the intra-articular BMC injections are safe procedures and no adverse events were reported [118]. In a prospective single-blind, placebo-controlled trial, 25 patients with bilateral knee OA and a median age of 60 years were randomized to receive BMC into one knee and saline placebo into the contralateral knee, thereby utilizing each patient as his/her own control. Safety data, effect of pain relief, knee function (Osteoarthritis Research Society International) measures, and the visual analog scale (VAS) for pain were observed until 6 months after the injections [119]. However, no differences between the two groups were observed. Of interest in this study was that the final injectate composition consisted of a mix of BMC and BMPF suspension. However, the eventual consequences of diluting BMC with BMPF on outcomes were not discussed. In another case series by Kim et al., a more invasive treatment approach was used. BMC was mixed with adipose tissue as a multi-tissue preparation for knee OA injections, in patients with a mean age of 60.7 years. At 9-month follow-up,

*DOI: http://dx.doi.org/10.5772/intechopen.91310*

**7.1 Knee osteoarthritis**

*The Rationale of Autologously Prepared Bone Marrow Aspirate Concentrate for use… DOI: http://dx.doi.org/10.5772/intechopen.91310*

non-stem cell cellular components in the treatment vial might have significant roles regarding behavior and function of MSCs. Recently, the cellular variances were confirmed in a systematic review, evaluating BMC studies in musculoskeletal pathologies [53]. Presumably, as postulated by numerous authors, the variances in BMC cellular compositions have a significant effect on the biological activity and regenerative potency of the treatment specimen, and these inconsistencies impact clinical outcomes [111, 113]. Unfortunately, an exact understanding of the underlying signaling relationships is not completely understood [114].

## **7. Bone marrow-derived mesenchymal cells in musculoskeletal disorders**

The use of autologous BM-derived MSCs for the treatment of a variety of musculoskeletal ailments is progressing significantly. Literature findings demonstrate positive outcomes after regenerative medicine MSC applications, in particular in joints, tendons, and bone, and hold great promise for future MSK-D applications, especially if more research and larger clinical trials are performed, focusing on cell validation processes and elucidating on potential dose responses.

#### **7.1 Knee osteoarthritis**

*Regenerative Medicine*

**24**

**Figure 12.**

significant differences occur. Centrifugation foremost significantly increases cells who take part in regenerative processes when compared to the BMA-MC product. In contrast the non-regenerative RBCs and PFH concentrations are significantly reduced in the treatment vial, while maintaining a higher cell viability after centrifugation. Our findings, with regard to cellular enrichments comparing a BMA with a BMC, are in agreement with others [41, 110], but not regarding RBC content and PFH. The cell concentrations are not only depending on the centrifugation protocols and the final BMC volume but are contingent of a meticulously executed BMA procedure, maintaining high cell viability, with minimal cell destruction.

*Pathophysiological effects and reactions of RBCs in BMC vials. In absence of scavengers and compensatory mechanisms, PFH split products can lead to toxic consequences like inflammation and prooxidant effects, endothelial cell dysfunction, and vasoconstriction. Biological treatment specimen, containing high concentrations of RBCs, will lead to RBC cell membrane disruption (eryptosis,) releasing macrophage migration inhibitory factor (MIF) (courtesy of P. Everts and modified from Schaer et al. [109]).*

Currently, eight BMC harvesting devices are available on the market, producing different formulations of BMC and tissue viabilities and yielding different cellular concentration characteristics [111, 112]. As such, BMC preparations may vary widely regarding HSCs, MSCs, progenitors, platelet growth factors, and RBC content. Given this heterogeneity, the impact of BMC therapies on tissue regeneration may vary greatly. Explicitly, it is important to understand that the BMC

**6.3 Not every bone marrow concentrate is born equal**

In this section we will present several clinical studies in which autologous, heterogenous BMC was used as a regenerative biologic to treat a variety of musculoskeletal disorders [42, 115]. Studies reporting on similar pathologies using BM-derived/ cultured MSCs are not mentioned as it has been reported that these technologies have different biomedical properties and extraction methods [116] and potentially possess new challenges and indications, when compared to at POC prepared fresh autologous BMCs. In clinical settings, BMC has been exploited as an ortho-biological treatment option for a range of indications, like symptomatic focal femoral head osteonecrosis, OA of the knee and hip, focal chondral defects, as well as another MSK-D. The rationale to use autologous BMC in osteoarthritic (OA) joints and other indications is its potential in facilitating anti-inflammatory and anabolic effects after injection. Moreover, the heterogenous BMC cellular assortment is known for its angiogenetic properties, therefore contributing to chondrocyte metabolism and inducing homing of (progenitor) stem cells to the treated areas [117]. Rodriguez-Fotan and co-workers used a two-step BMC preparation protocol in patients with early onset of OA in the knee or hip (Kellgren-Lawrence grades I–II, Tönnis grades I–II, respectively), with BMA aspirated from the anterior iliac crest. After a single BMC injection, 63% of treated patients had improved clinical symptoms at 6-month postinjection. They concluded that the intra-articular BMC injections are safe procedures and no adverse events were reported [118]. In a prospective single-blind, placebo-controlled trial, 25 patients with bilateral knee OA and a median age of 60 years were randomized to receive BMC into one knee and saline placebo into the contralateral knee, thereby utilizing each patient as his/her own control. Safety data, effect of pain relief, knee function (Osteoarthritis Research Society International) measures, and the visual analog scale (VAS) for pain were observed until 6 months after the injections [119]. However, no differences between the two groups were observed. Of interest in this study was that the final injectate composition consisted of a mix of BMC and BMPF suspension. However, the eventual consequences of diluting BMC with BMPF on outcomes were not discussed. In another case series by Kim et al., a more invasive treatment approach was used. BMC was mixed with adipose tissue as a multi-tissue preparation for knee OA injections, in patients with a mean age of 60.7 years. At 9-month follow-up,

all patients showed clinical improvement, with satisfactory results in 70.7% of patients [120]. Remarkably, the authors found that patients with inferior treatment results had a greater severity of OA prior treatment, as they were marked at Kellgren-Lawrence grade IV, suggesting that advanced OA may be more restrained to BMC therapy. The side effects encountered in this study, joint inflammation and pain, were in accordance with data from Rodriguez-Fotan [118]. Recently, a similar (retrospective) study was executed by Mautner and associates. Patients were prospectively treated either with bone marrow aspirate concentrate (BMAC) or micro-fragmented adipose tissue (MFAT) injections, for symptomatic knee OA [121]. The follow-up responses consisted of 76 patients (with 106 knees). The Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, Emory Quality of Life (EQOL) questionnaire, and VAS for pain were compared with baseline scores for all patients, and outcomes between BMAC and MFAT groups were evaluated. Data demonstrated a significant improvement in joint function and VAS pain scores after both MFAT and BMAC injections. No significant difference between the two autologous biological groups was demonstrating that BM- or adipose tissue-derived ortho-biological injections resulted in similar functional improvements.
