Bone Marrow Aspiration in Regenerative Medicine: Biology, Preparation, Classification, and Clinical Applications a Comprehensive Evidence-Graded Review of 236 Primary Sources Spanning Marrow Cell Biology, Harvest Anatomy, Concentration Physics, Dose-Response, Orthopaedic and Non-Orthopaedic Outcomes, Safety, Regulation and Reimbursement

Table 3: Harvest sites, access, reported advantages and limitations.

Yield comparisons between sites are drawn from single-centre comparative studies with differing assays and aspiration protocols and should not be read as device-independent constants.

Needle design, powered devices and anticoagulation

Needle geometry and technique change the product. Comparative analysis of needle techniques has been published for the interventional setting [57], and the effect of draw volume through a lateral-port needle has been quantified [36]. Needle internal diameter and the number of side openings have been specified in technique descriptions from the group that developed the osteonecrosis grafting protocol [58], the influence of anatomical site on the qualitative and quantitative yield of aspiration has been analysed directly [59], and contemporary technique descriptions for orthopaedic harvest have been published in operative form [60]. Contraindications are set out in general reference sources, including severe bleeding diathesis as an absolute contraindication [61]. Powered aspiration and biopsy systems have been compared with manual technique in a randomised comparison and in a systematic review, with reduced procedure time and comparable or improved specimen adequacy [62,63]. Anticoagulant choice is not neutral: the choice of anticoagulant alters the character of the aspirate [64], and differences in cytotoxicity between anticoagulant and additive formulations have been demonstrated directly [65]. Short-term handling and storage conditions have been formally validated for marrow destined for cell processing, which is relevant whenever aspiration and injection are separated in time [66]. Anatomical and computed-tomographic studies define the safe corridor and the structures at risk [67], and pain during aspiration and its modifiable determinants have been characterised, including with pharmacological premedication [68,69].

Reporting standards, and how comprehensively they are ignored

The Minimum Information for Studies Evaluating Biologics in Orthopaedics checklist specifies the variables that must be reported for a marrow-derived product to be interpretable, and the DOSES framework provides a complementary descriptive taxonomy adopted by national bodies [70–72]. Adherence is poor and has been quantified repeatedly. In the audit of forty-six clinical studies of marrow concentrate, relative centrifugal force was reported in none, revolutions per minute in 20%, spin duration in 30%, quantitative composition in 30%, flow cytometry in 15%, a colony-forming assay in 15% and fold increase in 6.5% [6]. Only 42% of the checklist variables were reported in a parallel assessment [21], and comparable deficits have been documented for mesenchymal stromal cell preparation protocols [73], for shoulder marrow concentrate studies [74], and across orthopaedic biologics generally [75].

Figure 4: Reporting of processing variables across forty-six clinical studies of bone marrow aspirate concentrate. Relative centrifugal force, the only variable that determines what a centrifuge does to a cell suspension, was reported in none of the studies audited. Revolutions per minute, which is uninterpretable without the rotor radius, was reported four times more often than the quantity it is used to approximate.

Table 9: Musculoskeletal indications, best available evidence and the setting in which each use can be defended.

Recommended setting reflects the strength of the comparator in the best available study for each indication and the alignment between the claim made and the biology the tissue supports.

Two registered randomised trials will test the two most important open questions directly: whole unconcentrated aspirate against saline in the knee [154] and concentrated aspirate against a sham incision [155], with a further trial comparing marrow against adipose tissue [156]. Until those results are available, the appropriate description of intra-articular marrow concentrate to a patient is that it is statistically better than a weak comparator, has never been shown to be better than a strong one, and has not been shown to be inferior to any competing orthobiologic either.

Beyond the Musculoskeletal System

The non-orthopaedic literature deserves attention from musculoskeletal practitioners for one reason: it is where marrow-derived cell therapy has been tested with the largest sample sizes, the most rigorous blinding and the hardest endpoints, and the pattern of results there is a warning about how the musculoskeletal literature is likely to evolve.

Figure 10: Non-orthopaedic randomised evidence for marrow-derived cell therapy. Effect estimates for amputation in critical limb ischaemia, for mortality in heart failure, for healing in diabetic foot ulceration, for liver disease and for multiple sclerosis, with the point at which restriction to placebo-controlled trials collapses an apparent benefit to the null shown explicitly.

Critical limb ischaemia: the clearest demonstration of what blinding does

A meta-analysis of all randomised trials of autologous cell therapy in critical limb ischaemia found a reduction in amputation with an odds ratio of 0.54 and a 95% confidence interval of 0.34 to 0.87 [157]. When the analysis is restricted to placebo-controlled trials the estimate becomes a relative risk of 0.91 with a 95% confidence interval of 0.65 to 1.27, which crosses one [158]. The Cochrane review of the field is consistent with the conservative reading [159]. This is the single most instructive pair of results in the entire marrow literature: the same intervention in the same indication, positive when unblinded trials are included and null when they are not.

Cardiac disease

Meta-analytic estimates of left ventricular ejection fraction gain after marrow-derived cell therapy for myocardial infarction cluster in the range of two to three percentage points: 2.92% with a 95% confidence interval of 1.91 to 3.92 in one synthesis [160] and 2.55% in another, rising to 5.30% in the subgroup with baseline ejection fraction below 40% [161], with mobilisation strategies reviewed separately [162]. The Cochrane review of chronic ischaemic heart disease and heart failure reported a mortality relative risk of 0.42 with a 95% confidence interval of 0.21 to 0.87 in its primary analysis and an ejection fraction difference of 0.90 percentage points that was not significant [163]. The adequately powered trials, however, were neutral: the trial of intracoronary infusion in 375 patients found 3.26% versus 3.82% [164], and the pivotal cardiopoietic cell trial reported a Finkelstein-Schoenfeld statistic of 0.52 with p = 0.51 [165].

Figure 11: Cardiac outcomes: meta-analytic ejection fraction gains alongside the results of the adequately powered individual trials. Pooled estimates of two to three percentage points of ejection fraction gain coexist with neutral results in the largest and best-controlled individual trials in myocardial infarction, advanced heart failure, perianal fistula and multiple sclerosis.

Diabetic foot ulceration, liver disease, multiple sclerosis and Crohn perianal fistula

Diabetic foot ulceration produces the largest reported effect in the non-orthopaedic literature, with an odds ratio for healing of 4.64 and a 95% confidence interval of 3.11 to 6.90 [166]; the caveat is that wound care trials are among the hardest to blind and the comparator is heterogeneous. The Cochrane review of cell therapy in liver disease found a relative risk of 0.52 with a 95% confidence interval of 0.24 to 1.11, which does not exclude the null [167]. In multiple sclerosis, the mesenchymal stromal cell trial enrolling 144 patients reported an effect estimate of 0.94 with a 95% confidence interval of 0.58 to 1.50 [168]. For Crohn perianal fistula the second pivotal trial of the allogeneic adipose product enrolled 568 patients and reported a difference of 2.4% with p = 0.571 [169]; the product had been authorised in 2018 and its authorisation was subsequently withdrawn [170].

Craniofacial, neurological and ophthalmic applications

Three further fields deserve brief mention because they illustrate both the breadth of the attempts made and the consistency of the evidential ceiling. In craniofacial and oral reconstruction, marrow concentrate combined with a xenogeneic graft has been evaluated in maxillary sinus augmentation [171], a comparison of two concentrate concentrations in the same procedure has been published [172], and a systematic review with meta-analysis of cell therapy for orofacial bone regeneration provides the pooled appraisal [173]. In stroke, a meta-analysis of randomised trials of mesenchymal stromal cell therapy has been reported [174]. In retinitis pigmentosa, intravitreal administration of marrow-derived cells has been evaluated with quality-of-life endpoints [175]. None of these fields has produced an adequately powered placebo-controlled demonstration of benefit, and all are appropriately described as research.

Where marrow-derived cell therapy is genuinely approved

It is important to distinguish the point-of-care aspirate from manufactured cell products, because the approvals belong entirely to the latter. Haematopoietic transplantation for malignant and non-malignant disease is standard of care [176,177]. A mesenchymal stromal cell product for steroid-refractory acute graft-versus-host disease was approved in December 2024 [178]. A manufactured marrow-derived product has been approved in India [119]. Manufacturing, potency and release testing for such products involve controls that have no counterpart in a point-of-care device [179–185], and extracellular vesicle products remain unapproved and subject to specific regulatory attention [186,187].

Table 15: Research agenda, ordered by the clinical uncertainty each question would resolve per unit of research effort.

Registered trial identifiers for the items marked as in progress are cited in the corresponding sections of the text.

Conclusion

Bone marrow aspiration is a safe, technically demanding procedure that yields a biologically active fluid whose most abundant components are not the ones invoked to justify its use. The defensible clinical applications today are those in which the marrow acts as an osteogenic graft adjunct to a mechanically stabilised construct, and core decompression with marrow grafting in pre-collapse osteonecrosis of the femoral head. Intra-articular injection and surgical augmentation are reasonable inside a registry or a trial, with explicit disclosure that superiority over a strong comparator has never been demonstrated. Intradiscal, intraosseous, systemic and stem cell branded uses are research activities, and in Brazil the addition of marrow concentrate to platelet-rich plasma outside approved research is expressly prohibited.

Three commitments would change the trajectory of this field more than any new product. Report relative centrifugal force and spin duration instead of revolutions per minute, and report the harvest and processing variables that existing checklists already specify. Compare against strong comparators, including saline, and publish the result whichever way it falls. And describe the product accurately to patients and to colleagues: a five-fold enrichment of a population present at one per thirty thousand nucleated cells is a legitimate biological intervention and it is not a stem cell treatment. The credibility of orthobiologics depends less on the next trial than on whether this field is willing to describe what it is already doing.

Declarations

Funding

No financial support for this work.

Conflicts of interest

No conflict of interest for any author: including consultancy, speaker fees, equity, royalties and device or biologics industry relationships.

Ethics statement

This work is a narrative review of published literature and does not involve new human participants, animals, or identifiable patient data. Institutional review board approval was therefore not required.

Author contributions

All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.

Data availability

Data availability statement: all data discussed in this review are contained within the cited publications and regulatory documents.

Acknowledgements

None.

Use of artificial intelligence

Use of artificial intelligence-assisted tools in literature organization and comparison tables, with human authors retaining full responsibility for the content.

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40. Hernigou P, Homma Y, Flouzat Lachaniette CH, Poignard A, Allain J, Chevallier N, et al. Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. Int Orthop. 2013;37(11):2279–87. In 30 adults aspirated bilaterally, a 10-mL syringe gave on average a 300% higher progenitor concentration than a matched 50-mL syringe (p < 0.01). 
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42. Mormone E, et al. Comparison of bone marrow aspirate from the posterior iliac crest and the proximal tibia. J Transl Med. 2024;22:1101. Marrow purity 71 versus 30% (p = 0.002), mononuclear cells 7.10 versus 3.58 x 10^6/mL (p = 0.005) and platelets 189.5 versus 64.5 x 10^6/mL (p < 0.001) in favour of the crest; more than half of tibial samples contained no detectable mesenchymal cells and two of 15 tibial harvests produced non-displaced fractures (13.3%, p < 0.001). 
43. Anz AW, Sherman BJ, et al. Bone marrow aspirate from the proximal humerus versus the posterior superior iliac spine. Arthroscopy. 2022;38(4):1110–14. In 12 patients the iliac site gave 55.9 versus 18.7 x 10^6 nucleated cells per mL (3.0-fold, p = 0.014) and 32.5 versus 3.9 colony-forming units per mL (8.3-fold, p = 0.024) with a shorter harvest time (5.6 versus 11.0 min, p = 0.043). 
44. Muench LN, Baldino JB, Berthold DP, et al. Proximal humerus bone marrow aspiration: sequential aliquot analysis. BMC Musculoskelet Disord. 2019;20:543. Four consecutive 10-cc aliquots fell from 30.7 plus or minus 23.5 to 3.0 plus or minus 4.3 x 10^6 nucleated cells per cc and from 742.0 plus or minus 885.9 to 39.3 plus or minus 77.9 colony-forming units per cc (p < 0.001) while concentrate volume was unchanged. 
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46. Cavallo C, et al. Bone marrow aspirate concentrate quality is affected by age and harvest site. Knee Surg Sports Traumatol Arthrosc. 2023;31:2140–51. Mononuclear cells per mL were 3.8 x 10^7 in young versus 1.2 x 10^7 in older patients (p < 0.0005); iliac crest colony-forming unit-fibroblast at day 10 was 15.9 versus 0.6 for proximal tibia (p = 0.001). 
47. Sugaya H, Yoshioka T, Kato T, Taniguchi Y, Kumagai H, Hyodo K, et al. Comparative analysis of cellular and growth factor composition in bone marrow aspirate concentrate and platelet-rich plasma. Bone Marrow Res. 2018;2018:1549826. Colony-forming unit-fibroblast rose from 31.6 to 196 per mL (6.0-fold), basic fibroblast growth factor 67.8 versus 10.7 pg/mL in favour of the marrow product (p < 0.001), while platelet-derived growth factor BB, vascular endothelial growth factor, transforming growth factor beta 1 and bone morphogenetic protein 2 did not differ. 
48. Hyer CF, Berlet GC, Bussewitz BW, Hankins T, Ziegler HL, Philbin TM. Quantitative assessment of the yield of osteoblastic connective tissue progenitors in bone marrow aspirate from the iliac crest, tibia and calcaneus. J Bone Joint Surg Am. 2013;95(14):1312–16. Iliac crest exceeded tibia and calcaneus (p < 0.0001); age, sex, tobacco use and diabetes were not predictive. 
49. McDaniel JS, Antebi B, Pilia M, Hurtgen BJ, Belenkiy S, Necsoiu C, et al. Quantitative assessment of optimal bone marrow site for the isolation of porcine mesenchymal stem cells. Stem Cells Int. 2017;2017:1836960. Iliac crest yielded 623.7 colony-forming units per mL
50. Encinas R, et al. Calcaneal bone marrow aspiration for orthobiologic harvest: safety and donor-site morbidity. Foot Ankle Spec. In 45 procedures with a mean aspirate volume of 10.3 mL, 32 of 45 patients (71.1%) had no pain at a mean 12.3 months, with no infections, nerve injuries, fractures, haematomas or deaths; a cited series of 548 calcaneal procedures likewise reported no nerve injury, infection or fracture. 
51. McLain RF, Fleming JE, Boehm CA, Muschler GF. Aspiration of osteoprogenitor cells for augmenting spinal fusion: comparison of progenitor cell concentrations from the vertebral body and iliac crest. J Bone Joint Surg Am. 2005;87(12):2655–61. In 21 patients with 168 paired aspirations, vertebral nucleated cells were 19.76 versus 16.95 x 10^6/cc (p = 0.05) and progenitor concentration 465.67 versus 356 per cc (p = 0.05). 
52. Saluja A, Saluja A, Saluja R. Fluoroscopically guided aspiration of bone marrow from the posterior superior iliac spine: a novel technique. J Orthop Surg Tech. 2024;7(1):572–78. Forty-seven patients followed for at least two years had no vascular injury, nerve injury, persistent pain or haematoma. 
53. Shapiro SA, Arthurs JR. Bone marrow aspiration for regenerative orthopaedic intervention: technique with ultrasound guidance for needle placement. Regen Med. 2017;12(8):917–28. All 32 needle passes across eight iliac crests of four cadaver pelves lay in safe zones; insertion should be limited to 4 cm from the posterior superior iliac spine without fluoroscopy or computed tomography, and ultrasound cannot assess depth once the needle has entered bone. 
54. Lana JF, Pires L, Macedo A, et al. Lateral and posterolateral iliac crest approach for bone marrow aspirate harvest in regenerative orthopaedic applications. J Orthop Surg Res. 2026;21:162. Sixty-three procedures with a 13-gauge cannula and 4-mL draws under local anaesthesia; correct subendosteal positioning in all cases and no immediate complications; mean posterior-crest-to-sacral-canal distance 18.4 mm and a physiological ceiling of 20 mL per kg body weight. 
55. Piuzzi NS, Muschler GF, et al. Bone marrow aspiration technique. JBJS Rev. 2018;6(11):e4 (technique supplement). Beveled 8-gauge 7-inch needle, aspiration sites dispersed 0.5–1 cm apart from a single cortical entry, 1–2 mL per site into a 10-mL syringe preloaded with 1 mL of sodium heparin 1000 IU/mL. 
56. Tomasian A, Jennings JW. Bone marrow aspiration and biopsy: techniques and practice implications. Skeletal Radiol. 2021. Complication rates of 0.08–0.12% in two large British surveys, 0.3% immediate complications in 775 fluoroscopy-guided cases, no complications in 981 computed-tomography-guided procedures including 33 with platelets below 20,000 per microlitre, and a dry-tap rate of 2.0–6.6%. 
57. Kyriakides PW, Lutz GE, Kyriakides C, et al. Comparative analysis of different needle techniques for bone marrow harvest. J Regen Med. 2024;13(4). Bilateral within-patient design in 29 patients: 5 mL drawn with an 11-gauge multiport needle gave total nucleated cells 46.4 plus or minus 4.6 versus 33.8 plus or minus 4.51 x 10^6/mL (p < 0.001) and colony-forming unit-fibroblast 4469 plus or minus 583 versus 2676 plus or minus 626 per mL (p < 0.0001) against a single-port Jamshidi, with no difference in CD34-positive cells (p = 0.1193); an earlier 10-mL comparison favoured the single-port device. 
58. Hernigou P. Bone marrow aspiration technique, concentration methods and applications. 2011. Needle internal diameter 1.5 mm, 2–7 cc per bevel position with 45 degree rotations; maximum 150 cc from the anterior and 250 cc from the posterior iliac crest. 
59. Marx RE, Tursun R. A qualitative and quantitative analysis of autologous human multipotent adult stem cells derived from three anatomic areas by marrow aspiration. J Oral Maxillofac Surg. 2013;71(10):1808–13. Anterior and posterior ilium were equivalent with a concentration factor of 6.5 plus or minus 1.0, whereas the tibial plateau gave less than half the nucleated, CD44-positive and CD105-positive counts. 
60. Allahabadi S, Chapman RS, Fortier LM, et al. Bone marrow aspirate concentrate harvest techniques for orthopaedic applications. Arthrosc Tech. 2024;13(2):102850.
61. Bone marrow aspiration and biopsy. StatPearls. NCBI Bookshelf; updated 2023. Severe bleeding diatheses are absolute contraindications; retroperitoneal or gluteal haemorrhage may follow internal iliac or superior gluteal artery injury. 
62. Bucher CM, Lehmann T, Tichelli A, Tzankov A, Dirnhofer S, Passweg J, et al. Comparison of a powered bone marrow biopsy device with a manual system: results of a prospective randomised controlled trial. J Clin Pathol. 2013;66(1):24–28. Sixty procedures showed no difference in diagnostic cylinders, cylinder length, procedure time or aspirate quality; the only significant advantage was less pain in the unsedated subgroup (median 3 versus 7, p = 0.015). 
63. Voigt J, Mosier M. A powered bone marrow biopsy system versus manual methods: a systematic review and meta-analysis of randomised trials. J Clin Pathol. 2013;66(9):792–96. Across five randomised trials powered insertion reduced pain by 6.57 visual analogue points (95% CI -12.93 to -0.22; p = 0.04), shortened the procedure by 85.35 s and lengthened the core by 3.65 mm, with an adverse-event risk ratio of 3.56 (0.59–21.42). 
64. Dregalla RC, Herrera JA, Koldewyn LS, Donner EJ. The choice of anticoagulant influences the characteristics of bone marrow aspirate concentrate and mesenchymal stem cell bioactivity in vitro. Stem Cells Int. 2022;2022:8259888. Heparin 100 U/mL versus 15% sodium citrate gave colony-forming unit-fibroblast 1037 plus or minus 153 versus 187 plus or minus 45 per mL (p = 0.0001) and viability 98.50 versus 95.18% (p = 0.0008); heparin 100 U/mL also outperformed 1000 U/mL on nucleated cells (p = 0.0013), viability (p = 0.0091) and colony-forming units (p = 0.0043). 
65. Kubrova E, Su M, Galeano-Garces C, Galvan ML, Jerez S, Dietz AB, et al. Differences in cytotoxicity of lidocaine, ropivacaine and bupivacaine on the viability and metabolic activity of human adipose-derived mesenchymal stem cells. Am J Phys Med Rehabil. 2021;100(1):82–91. Lidocaine 8, 5 and 2.5 mg/mL and bupivacaine 2.5, 1.25 and 0.313 mg/mL reduced viability below 50% beyond 6 hours; ropivacaine was the least cytotoxic agent.
66. Kao GS, Kim HT, Daley H, et al. Validation of short-term handling and storage conditions for marrow and peripheral blood stem cell products. Transfusion. 2011;51(1):137–47. Marrow products maintained equivalent viability at 4 and 20 degrees Celsius for up to 72 hours with mean viable CD34-positive recovery above 75% at 4 degrees, and citrate-dextrose anticoagulation was preferred over heparin to limit lactate accumulation.
67. Konda B, Pathak S, Edwin I, et al. Safe and successful bone marrow biopsy: an anatomical and computed-tomography-based cadaver study. Am J Hematol. 2014;89(10):943–46. A trajectory reoriented laterally toward the ipsilateral anterior superior iliac spine caused less neurovascular damage and avoided the sacroiliac joint compared with a perpendicular path. 
68. Gendron N, Zia Chahabi S, Poenou G, et al. Pain assessment and factors influencing pain during bone marrow aspiration: a prospective study. PLoS One. 2019;14(8):e0221534. Among 448 patients and 461 procedures the median numerical pain rating was 3.5 for sternal versus 2.5 for iliac crest aspiration (p < 0.0001); lidocaine infiltration reduced the score by 1.06 points (95% CI -1.92 to -0.20; p = 0.0158) whereas anaesthetic cream alone did not, and anxiety was the dominant determinant. 
69. Cerchione C, Martinelli G, Picardi M, et al. Combined oral fentanyl citrate and midazolam as premedication for bone marrow aspiration and biopsy in patients with haematological malignancies: a randomised, controlled, patient-blinded clinical trial. J Clin Med. 2020;9(2):395. Sedoanalgesia did not improve the aspiration phase itself (3.54 versus 3.63) and benefited only the trephine and recovery phases. 
70. Murray IR, Geeslin AG, Goudie EB, Petrigliano FA, LaPrade RF. Minimum Information for Studies Evaluating Biologics in Orthopaedics (MIBO): platelet-rich plasma and mesenchymal stem cells. J Bone Joint Surg Am. 2017;99(10):809–19. Delphi process with 23 of 24 experts completing three rounds, producing a 23-statement platelet-rich plasma checklist and a 25-statement mesenchymal stromal cell checklist. 
71. Murray IR, Chahla J, Safran MR, Krych AJ, Saris DBF, Caplan AI, LaPrade RF. International expert consensus on a cell therapy communication tool: DOSES. J Bone Joint Surg Am. 2019;101(10):904–11. Thirty-four of 36 invited experts; all 27 final items reached consensus; donor, origin and site of delivery reached 100, 100 and 97% agreement and exhibited cell characteristics 85%. 
72. British Orthopaedic Association. Orthobiologics: scientific background. Adopts the DOSES framework and states that the term stem cell is now discouraged in the orthobiologics setting. 
73. Piuzzi NS, et al. Reporting of mesenchymal stem cell preparation protocols and composition: a systematic review of the clinical orthopaedic literature. Am J Sports Med. 2019. Studies reported only 52% (range 30–80%) of the variables that may critically influence outcome. 
74. Hedbany D, et al. Adherence of bone marrow aspirate concentrate studies of the shoulder to Minimum Information for Studies Evaluating Biologics in Orthopaedics guidelines. Clin Shoulder Elb. 2025;29(1):105–14. Mean adherence 52.2 plus or minus 12.1% (range 30.4–76.1%), no category reaching 80%, and no improvement after 2017 (p = 0.074). 
75. Butler JJ, et al. Adherence to Minimum Information for Studies Evaluating Biologics in Orthopaedics guidelines in bone marrow aspirate concentrate studies of the foot and ankle. Foot Ankle Surg. 2024. Nine studies and 356 patients; adherence 42.8 plus or minus 5.2% with no study reaching 50%. 
76. Pösel C, Moller K, Fröhlich W, Schulz I, Boltze J, Wagner DC. Density gradient centrifugation compromises bone marrow mononuclear cell yield. PLoS One. 2012;7(12):e50293. Mononuclear recovery was 25.6 plus or minus 5.8% for Ficoll, 51.5 plus or minus 2.3% for Percoll and 72.3 plus or minus 6.7% for immunomagnetic granulocyte depletion; colony-forming unit-fibroblast frequency in lysed whole marrow was 0.00007 plus or minus 0.00002% and no colony-forming unit-fibroblast was detected in any gradient-separated fraction; approximately 30% of haematopoietic and 55% of mesenchymal progenitors are lost during mononuclear isolation. 
77. Hermann PC, Huber SL, Herrler T, von Hesler C, Andrassy J, Kevy SV, et al. Concentration of bone marrow total nucleated cells by a point-of-care device provides a high yield and preserves their functional activity. Cell Transplant. 2008;17(9):1059–69. Nucleated cell yield was 2.4 times higher than Ficoll (range 2.1–3.0), platelet retention 74.3 plus or minus 14.9% versus below 0.5% for Ficoll, bedside processing time 15 minutes, migratory activity 164 plus or minus 66% of Ficoll cells (p = 0.007) and murine hindlimb perfusion 0.64 plus or minus 0.16 versus 0.46 plus or minus 0.15 (p = 0.003). 
78. Gaul F, Bugbee WD, Hoenecke HR, D'Lima DD. A review of commercially available point-of-care devices to concentrate bone marrow for the treatment of osteoarthritis and focal cartilage lesions. Cartilage. 2019;10(4):387–94. Nucleated cell recovery ranged from 32.6 plus or minus 13.7% (Magellan) to 80% (Celling) and connective tissue progenitors per square centimetre from 0.4 to 2.3; no independent peer-reviewed haematocrit or red-cell-reduction data and no device costs were available for any system. 
79. Scillia AJ, et al. Benchmark comparison of bone marrow aspiration systems: increased progenitor cell concentrations achieved without centrifugation using a novel filtration design with high surface area. Cureus. 2026;18(6):e110747. Five donors gave nucleated cells 102.2 plus or minus 66.0 x 10^6/mL, colony-forming unit-fibroblast 15,145 plus or minus 15,131 per mL and viability 96.9 plus or minus 1.4%; the study was descriptive, industry-funded and unrandomised. 
80. Hegde V, Shonuga O, Burch S, Besho R, Chojnowski D, Bostrom MP, et al. A prospective comparison of three approved systems for autologous bone marrow concentration demonstrated non-equivalency in progenitor cell number and concentration. J Orthop Trauma. 2014;28(10):591–98. Forty patients underwent bilateral iliac aspiration with randomised device allocation; the three commercial systems were declared non-equivalent for connective tissue progenitor number, concentration and percentage yield. 
81. Degen RM, Bernard JA, Oliver KS, Dines JS. Commercial separation systems designed for preparation of platelet-rich plasma yield differences in cellular composition. HSS J. 2017;13(1):75–80. Platelet concentration ranged from 1,129 plus or minus 264 to 2,310 plus or minus 524 x 10^3 per microlitre and haematocrit from 1.1 plus or minus 0.4% to 28.9 plus or minus 4.4% across six commercial systems processing the same donor blood. 
82. Scarpone M, Kuebler D, Chambers A, De Filippo CM, Amatuzio M, Ichim TE, et al. Isolation of clinically relevant concentrations of bone marrow mesenchymal stem cells without centrifugation. J Transl Med. 2019;17:10. An aspiration-only lateral-port system yielded fewer nucleated cells than a centrifuged comparator (31.5 plus or minus 15.5 versus 66.1 plus or minus 20.5 x 10^6/mL, p = 0.0001) but more colony-forming unit-fibroblast (1583 plus or minus 858 versus 797 plus or minus 509 per mL, p = 0.0346); a 30-patient series gave 2885 plus or minus 1716 colony-forming units per mL with an inverse correlation with age (r = -0.4689, p = 0.009). 
83. Dragoo JL, Guzman RA. Evaluation of the consistency and composition of commercially available bone marrow aspirate concentrate systems. Orthop J Sports Med. 2020;8(1):2325967119893634. Percentage colony-forming unit-fibroblast recovery was 25.8, 47.4 and 82.4 for three devices (p < 0.001) while fold concentration did not differ (p = 0.689). 
84. Cassano JM, Kennedy JG, Ross KA, Fraser EJ, Goodale MB, Fortier LA. Bone marrow concentrate and platelet-rich plasma differ in cell distribution and interleukin 1 receptor antagonist protein concentration. Knee Surg Sports Traumatol Arthrosc. 2018;26(1):333–42. Interleukin 1 receptor antagonist was 13,432 pg/mL in marrow concentrate versus 588 pg/mL in platelet-rich plasma (p = 0.0018) in 29 patients, while transforming growth factor beta 1, platelet-derived growth factor and platelet counts did not differ. 
85. Ziegler CG, et al. Characterisation of growth factors, cytokines and catabolic molecules in bone marrow aspirate, bone marrow concentrate, leukocyte-rich and leukocyte-poor platelet-rich plasma. Orthop J Sports Med. 2019;7(7 suppl 5):2325967119S00284. Median interleukin 1 receptor antagonist was 143 in whole blood, 48.9 in leukocyte-poor and 257.8 in leukocyte-rich platelet-rich plasma, 463 in aspirate and 796.6 in marrow concentrate, with marrow concentrate exceeding all others (p < 0.0009). 
86. Schäfer R, et al. Quantitation of progenitor cell populations and growth factors after bone marrow aspirate concentration. J Transl Med. 2019;17:115. Nucleated cells were concentrated approximately tenfold, red cells were depleted, CD34-positive cells were not concentrated at all (0.809-fold, p = 0.71 and 1.088-fold, p = 0.93) and colony-forming unit-fibroblast enrichment ranged from 4.4- to 41.2-fold across donors.
87. Long S, Maleas G, Belacic ZA, Quam VG, Durgam S. Equine bone marrow aspirate and bone marrow aspirate concentrate are enriched with interleukin 1 receptor antagonist protein. Am J Vet Res. 2025;86(5):ajvr.24.12.0380. Donor-matched interleukin 1 receptor antagonist was 21 times higher in concentrate than aspirate (P < 0.0005) and 117 times higher than in leukocyte-rich platelet-rich plasma (P < 0.0001), and tracked leukocyte count (R = 0.673). 
88. Ragni E, de Girolamo L, Grieco G, Piccolo S. Secretome and extracellular vesicle signatures in bone marrow-derived mesenchymal stromal cells after expansion in standard and next-generation media. Extracell Vesicles Circ Nucl Acids. 2025;6:195–215. Ninety-eight soluble proteins were common to all three media; hepatocyte growth factor differed 208-fold between conditions while identity markers were unchanged. 
89. Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem and stromal cells. Stem Cell Res Ther. 2016;7:7. Up to 80% of injected cells are trapped in the lungs within minutes with a pulmonary half-life of approximately 24 hours; intra-arterial delivery to inflamed joints leaves 15% at one month and 1.5% beyond six months. 
90. Lana JFSD, Purita J, Paulus C, Huber SC, Rodrigues BL, Rodrigues AA, et al. Contributions for classification of platelet-rich plasma: proposal of a new classification, MARSPILL. Regen Med. 2017;12(5):565–74. The eight axes describe method, activation, red cells, spin, platelet fold-increase, image guidance, leukocytes and light activation, all defined for platelet products; no bone marrow data are presented, so application to marrow concentrate is an extrapolation. 
91. Purita J, Lana JFSD, Kolber M, Rodrigues BL, Mosaner T, Santos GS, et al. Bone marrow-derived products: a classification proposal: bone marrow aspirate, bone marrow aspirate concentrate or hybrid? World J Stem Cells. 2020;12(4):241–50. Aspirate, concentrate or hybrid is combined with eight escalating levels of characterisation from collection description to functional assay, written for example as C1-3;5; the authors note that no study defines the optimal centrifugal force and time for bone marrow. 
92. de Girolamo L, Laver L, Andriolo L, Andia I, Nehrer S, Kon E, et al. ESSKA Orthobiologic Initiative (ORBIT) Part 2: bone marrow and adipose tissue-derived products for the treatment of knee osteoarthritis. Complete consensus report, 2024. Fifty-one experts from 21 countries and 36 peer-review delegates from 20 societies; aspirations above 2 mL and syringes above 10 mL increase peripheral blood contamination (Q18, Grade C, agreement 8.3 plus or minus 0.7); a properly harvested aspirate approximates single-spin concentrate and double-spin concentrate is recommended for knee osteoarthritis (Q13, Grade D); MIBO is endorsed for characterisation (Q16, Grade D); combination with platelet-rich plasma is not recommended (Q23, Grade C); no consensus was reached on dose (Q19, Grade C). 
93. American Academy of Orthopaedic Surgeons. Technology overview: concentrated bone marrow aspirate for knee osteoarthritis. Adopted 3 December 2021. Twelve articles were included from 47 full texts; no single standardised processing device, centrifuge brand or processing protocol could be identified across studies, no study identifies an optimal cell dose, and the document argues that the literal quantity of mesenchymal cells in concentrated aspirate is unlikely to be of significant consequence. 
94. Hernigou P, Poignard A, Beaujean F, Rouard H. Percutaneous autologous bone-marrow grafting for nonunions: influence of the number and concentration of progenitor cells. J Bone Joint Surg Am. 2005;87(7):1430–37. Sixty atrophic tibial nonunions received about 20 cm3 of concentrate; union occurred in 53 of 60 patients whose graft contained more than 1500 progenitors per cm3 and averaged 54,962 plus or minus 17,431 total progenitors, whereas the 7 failures received 634 plus or minus 187 per cm3 (p = 0.001) and 19,324 plus or minus 6843 total (p < 0.01). 
95. Centeno CJ, Al-Sayegh H, Bashir J, Goodyear S, Freeman MD. A dose response analysis of a specific bone marrow concentrate treatment protocol for knee osteoarthritis. BMC Musculoskelet Disord. 2015;16:258. In 373 patients and 424 knees a threshold of 4 x 10^8 total cells separated a numeric pain score of 1.6 above threshold from 3.2 below.
96. Centeno CJ, et al. The influence of bone marrow concentrate colony-forming unit-fibroblast dose on outcomes after intra-articular knee injection. Int Orthop. 2022. A threshold near 18 x 10^3 colony-forming unit-fibroblast per mL was identified in 65 patients and 72 knees with a receiver-operating-characteristic area under the curve of 0.677, indicating weak discrimination.
97. Chaput CD, et al. Colony-forming unit-fibroblast dose and fusion after anterior cervical discectomy and fusion with bone marrow aspirate concentrate. PLoS One. 2018. Twenty-four patients and 31 levels achieved 86.7% fusion with a 3.94-fold concentration and a colony frequency window of 3.0 x 10^-6 to 5.83 x 10^-5 per mononuclear cell.
98. Muschler GF, Nitto H, Matsukura Y, Boehm C, Valdevit A, Kambic H, et al. Spine fusion using cell matrix composites enriched in bone marrow-derived cells: selective cell retention. Preparation increased nucleated cells 2.3 plus or minus 0.5-fold and connective tissue progenitors 5.6 plus or minus 3.9-fold with a progenitor attachment efficiency of 61 plus or minus 14%; in 12 dogs and 36 fusion sites the union rate was 67% for enriched matrix, 50% for matrix plus unprocessed aspirate and 17% for matrix alone (p = 0.018). 
99. Muschler GF, Nitto H, Matsukura Y, et al. Spine fusion using cell matrix composites enriched in bone marrow-derived cells. Clin Orthop Relat Res. 2003;(407):102–18. An enriched bone-matrix composite combined with a bone marrow clot was superior to enriched matrix alone in union score, fusion volume and fusion area. 
100. American Academy of Orthopaedic Surgeons. Technology overview: concentrated bone marrow aspirate for knee osteoarthritis. Studies comparing concentrated bone marrow aspirate with placebo did not identify statistically significant improved outcomes beyond one week, and two high-quality studies found concentrated bone marrow aspirate with platelet-poor plasma no better than placebo saline for function, magnetic resonance cartilage appearance or pain; a reasonable estimate of equipment cost is on the order of more than US$1,000 per episode and the treatment is not covered by insurance. 
101. Ruane JJ, Ross A, Zigmont V, McClure D, Gascon G. A single-blinded randomised controlled pilot study of the effects of bone marrow aspirate concentrate and platelet-rich plasma versus hyaluronic acid for knee osteoarthritis. J Stem Cells Regen Med. 2021;17(1):3–17. Thirty patients treated; numerical pain rating fell by 3.13 versus 1.56 points, between-group difference -1.57 (95% CI -2.89 to -0.25; p = 0.02), while the 12-month Knee Injury and Osteoarthritis Outcome Score difference did not reach significance; the trial reported no centrifugal force, spin time, nucleated cell count, colony count or viability. 
102. Imam MA, Holton J, Ernstbrunner L, et al. A systematic review of the clinical applications and complications of bone marrow aspirate concentrate in the management of bone defects and nonunions. Int Orthop. 2017;41(11):2213–20. 
103. Han S, et al. Bone marrow aspirate concentrate injections for the treatment of knee osteoarthritis: a systematic review of randomised controlled trials. Orthop J Sports Med. 2024. Eight randomised trials with 937 patients gave pooled pain mean differences versus hyaluronic acid of 0.28 (95% CI -0.07 to 0.63) at 3 months, 0.38 (0.03 to 0.72) at 6 months and 0.48 (0.11 to 0.84) at 12 months, all below the authors' minimal clinically important thresholds of 15.4 points for knee osteoarthritis outcome score pain and 19.1 for visual analogue pain. 
104. Keeling LE, Belk JW, Kraeutler MJ, Kallner AC, Lindsay A, McCarty EC, et al. Bone marrow aspirate concentrate for the treatment of knee osteoarthritis: a systematic review. Am J Sports Med. 2022;50(8):2315–23. Eight studies and 299 knees followed for a mean 12.9 months showed significant improvement in 34 of 36 patient-reported outcomes but no superiority over platelet-rich plasma, microfragmented adipose tissue or placebo. 
105. Chandrashekar S, Jeyaraman M, Mounissamy P, Jeyaraman N, Khanna M, Gupta A. Safety and efficacy of bone-marrow aspirate concentrate in hip osteoarthritis: a systematic review. 2024. Five studies with 182 participants and follow-up of 3 to 12 months were identified, all case series or cohorts; no placebo-controlled randomised trial of marrow concentrate in hip osteoarthritis exists. 
106. Systematic review of bone marrow aspirate concentrate for knee osteoarthritis. Br Med Bull. 2025;153(1):ldae016. The superiority of bone marrow aspirate concentrate over other orthobiological treatments cannot be assessed because of conflicting results, and given its higher morbidity and cost it is not worthwhile to prefer it to other conservative treatments. 
107. Randomised comparison of bone marrow aspirate concentrate and viscosupplementation for knee osteoarthritis at 24 months. Bone marrow aspirate concentrate did not demonstrate clinically significant short-term superiority, with comparable clinical scores, failures, adverse events, radiographic evaluation, minimal clinically important difference achievement and patient treatment judgement. 
108. Anz AW, Hubbard R, Rendos NK, Everts PA, Andrews JR, Hackel JG. Bone marrow aspirate concentrate is equivalent to platelet-rich plasma for the treatment of knee osteoarthritis at 1 year. Orthop J Sports Med. 2020;8(2):2325967119900958. Ninety patients were randomised and 84 analysed; the International Knee Documentation Committee score rose from 45.0 to 64.3 with concentrate and 47.4 to 63.7 with leucocyte-rich platelet-rich plasma, with a significant time effect (p < 0.001) and no between-group difference. 
109. Boffa A, Di Martino A, Andriolo L, De Filippis R, Poggi A, Cenacchi A, et al. Bone marrow aspirate concentrate injections provide similar results versus viscosupplementation up to 24 months of follow-up in patients with symptomatic knee osteoarthritis: a randomised controlled trial. Knee Surg Sports Traumatol Arthrosc. 2022;30(12):3958–67. Visual analogue improvement was 2.2 plus or minus 2.6 versus 1.4 plus or minus 2.8 at 24 months (p = 0.002), a between-group difference of about 0.8 points confined to Kellgren-Lawrence grades 1 to 2, with failures 10.7% versus 12.5%. 
110. Dulic O, Rasovic P, Lalic I, Kecojevic V, Gavrilovic G, Abazovic D, et al. Bone marrow aspirate concentrate versus platelet-rich plasma or hyaluronic acid for the treatment of knee osteoarthritis. Medicina (Kaunas). 2021;57(11):1193. In 175 patients the concentrate exceeded hyaluronic acid on knee osteoarthritis outcome score pain (mean difference 15.3; p = 0.002) and International Knee Documentation Committee score (15.2; p = 0.002) but did not differ from platelet-rich plasma. 
111. Jin QH, Chung YW, Na SM, Ahn HW, Jung DM, Seon JK. Bone marrow aspirate concentration provided better results in cartilage regeneration to microfracture in knee of osteoarthritic patients. Knee Surg Sports Traumatol Arthrosc. 2021;29(4):1090–97. Forty-three microfracture cases were compared with 48 microfracture plus concentrate cases; the International Cartilage Repair Society repair assessment score favoured concentrate (p = 0.035) while pain, function and Western Ontario and McMaster scores did not differ. 
112. McCormack J, Underwood F, Slaven E, Cappaert T. The minimum clinically important difference on the Victorian Institute of Sport Assessment-Achilles and Lower Extremity Functional Scale for patients with insertional Achilles tendinopathy. In 15 patients the minimal clinically important difference was 6.5 points for the Victorian Institute of Sport Assessment-Achilles scale and 12 points for the Lower Extremity Functional Scale; the very small sample and insertional phenotype limit generalisation. 
113. Mautner K, Gottschalk M, Boden SD, et al. Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial. Nat Med. 2023;29(12):3120–6. In the MILES trial, 480 patients were randomised to bone marrow aspirate concentrate, umbilical cord mesenchymal stromal cells, adipose stromal vascular fraction or corticosteroid; no orthobiologic was superior to another or to corticosteroid at 12 months, with no magnetic resonance structural change. 
114. Jawanda H, Khan ZA, Warrier AA, et al. Platelet-rich plasma, bone marrow aspirate concentrate and hyaluronic acid injections outperform corticosteroids in pain and function scores at a minimum of 6 months as intra-articular injections for knee osteoarthritis: a systematic review and network meta-analysis. Arthroscopy. 2024;40(5):1623–36.e1. Across 48 studies and 9338 knees the surface under the cumulative ranking curve was 91.54 for platelet-rich plasma, 76.46 for marrow concentrate, 53.12 for hyaluronic acid, 15.18 for corticosteroid and 13.70 for placebo, with marrow concentrate contributing only about 2.5% of included studies. 
115. Vitali M, et al. Bone marrow versus adipose-derived cell therapy for knee osteoarthritis: an exploratory comparative study with CD34+ quantification. Indian J Orthop. 2025;59(12):2119–25. Both groups improved (p < 0.01) with no between-group difference at six months and no correlation between mesenchymal stromal cell quantity and efficacy; 30 of 30 marrow aspirates versus 2 adipose samples reached the culture threshold. 
116. Mohamed-Ahmed S, Fristad I, Lie SA, et al. Adipose-derived and bone marrow mesenchymal stem cells: a donor-matched comparison. Stem Cell Res Ther. 2018;9(1):168. Adipose-derived cells showed greater proliferation and adipogenic capacity, whereas bone marrow cells showed greater osteogenic and chondrogenic differentiation. 
117. Awad ME, et al. Efficacy and safety of mesenchymal stem cell therapy for knee osteoarthritis: a systematic review and meta-analysis of 28 randomised controlled trials. Clin Rheumatol. 2026;45(5):2905–42. Visual analogue scale mean difference was −1.67 (p = 0.007) and Knee Injury and Osteoarthritis Outcome Score pain +15.37 (p = 0.03), while Western Ontario and McMaster Universities Osteoarthritis Index and Whole-Organ Magnetic Resonance Imaging Score outcomes were non-significant; injection-site pain risk ratio was 2.04 (p = 0.0005). 
118. Kim SH, Djaja YP, Park YB, Park JG, Ko YB, Ha CW. Intra-articular injection of culture-expanded mesenchymal stem cells without adjuvant surgery in knee osteoarthritis: a systematic review and meta-analysis. Am J Sports Med. 2020;48(11):2839–49. Across six randomised trials the visual analogue scale mean difference was −13.55 (95% confidence interval −22.19 to −4.9) with no demonstrated cartilage benefit. 
119. Gupta PK, Maheshwari S, Cherian JJ, et al. Efficacy and safety of stempeucel in osteoarthritis of the knee: a phase 3 randomized, double-blind, multicentre, placebo-controlled study. Am J Sports Med. 2023;51(9):2254–66. In 146 patients, pooled allogeneic bone marrow mesenchymal stromal cells with hyaluronic acid reduced total Western Ontario and McMaster Universities Osteoarthritis Index score by 45.60% at 12 months (95% confidence interval −55.97 to −35.23, p < 0.001), with no worsening of deep medial femorotibial cartilage on T2 mapping. 
120. Lamo-Espinosa JM, Mora G, Blanco JF, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: four-year follow-up of a multicenter randomized controlled clinical trial. J Transl Med. 2018;16(1):213. Visual analogue scale improvement was significant at four years for both the 10 million and 100 million cell doses (p = 0.01 and p = 0.004). 
121. Hernigou P, Beaujean F. Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res. 2002;(405):14–23. Among 116 patients and 189 hips followed 5 to 10 years, only 9 of 145 pre-collapse hips progressed to arthroplasty compared with 25 of 44 post-collapse hips, and outcome correlated with the number of progenitors transplanted. 
122. Hernigou P, Bouthors C, Bastard C, Flouzat Lachaniette CH, Rouard H, Dubory A. Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: what better postpone knee arthroplasty at fifteen years? A randomised study. Int Orthop. 2021;45(2):391–99. In 60 patients and 120 knees a 40 mL concentrate averaging 5727 colony-forming units per mL was split between subchondral and intra-articular delivery; at a mean 15 years arthroplasty incidence was 1.3% versus 4.6% per knee-year (p = 0.01) and total knee arthroplasty was performed in 20% versus 70% of knees. 
123. Li M, Ma Y, Fu G, Zhang Z, Zhao Q, Zhou Y, et al. Ten-year follow-up results of the prospective, double-blinded, randomised, controlled study on autologous bone marrow buffy coat grafting combined with core decompression in patients with avascular necrosis of the femoral head. Stem Cell Res Ther. 2020;11:287. Mean survival was 78.1 versus 102.3 months (log-rank p = 0.029), the hazard ratio for buffy-coat treatment was 0.332 (p = 0.042) and for Ficat stage 3.283 (p = 0.028); at 120 months visual analogue score was 3.5 versus 1 (p = 0.001). 
124. Hu L, et al. Network meta-analysis of surgical treatments for osteonecrosis of the femoral head. Eighteen randomised trials and 11 treatments were compared; autologous bone graft plus marrow concentrate versus core decompression alone gave an odds ratio of 0.019 (95% CI 0.0012 to 0.25) for disease progression and ranked first by surface under the cumulative ranking curve, without a difference in arthroplasty conversion. 
125. Pawar N, Vaish A, Vaishya R. Core decompression and bone marrow aspirate concentrate injection for osteonecrosis of the femoral head: a scoping review. J Clin Orthop Trauma. 2021;24:101691. Across 612 hips of mean age 38.3 years followed 2 to 12 years, radiographic progression occurred in 23.5% and conversion to arthroplasty in 14.9%, with cell doses from 2 x 10^6 to 3.46 x 10^9. 
126. Pepke W, Kasten P, Beckmann NA, Janicki P, Egermann M. Core decompression and autologous bone marrow concentrate for treatment of femoral head osteonecrosis: a randomized prospective study. Orthop Rev (Pavia). 2016;8(1):6162. Centrifugation increased colony-forming unit counts without translating into a clinical difference.  https://pubmed.ncbi.nlm.nih.gov/27114808/
127. Hauzeur JP, De Maertelaer V, Baudoux E, Malaise M, Beguin Y, Gangji V. Inefficacy of autologous bone marrow concentrate in stage three osteonecrosis: a randomized controlled double-blind trial. Int Orthop. 2018;42(7):1429–35. Fifteen of 23 hips progressed to total hip replacement in both arms. 
128. ClinicalTrials.gov identifier NCT06123481. Core decompression with or without autologous bone marrow aspirate in early osteonecrosis of the femoral head: randomised double-blind trial of 192 participants, Johns Hopkins University. 
129. Chatterjee S, et al. Lumbar interbody fusion using a truss implant packed with bone marrow aspirate clot versus crushed cancellous homologous bone: a randomised trial. Int J Spine Surg. 2020;14(6):924–35. Endpoints included Oswestry Disability Index, visual analogue scales, EuroQol-5D, reoperations and independently assessed fusion on computed tomography at three months. 
130. Salamanna F, Barbanti Brodano G, Griffoni C, et al. Vertebral bone marrow clot as a three-dimensional multifunctional bioscaffold in instrumented posterior lumbar fusion: a prospective clinical pilot. Front Endocrinol (Lausanne). 2023;14:1245344. Ten consecutive patients were followed with visual analogue scale, Oswestry Disability Index and EuroQol at baseline, three and 12 months; the approach was safe and feasible. 
131. ClinicalTrials.gov identifier NCT05947175. Vertebral bone marrow clot in spinal surgery: randomised trial of 96 participants, Istituto Ortopedico Rizzoli. 
132. Buser Z, Hsieh P, Meisel HJ, Skelly AC, Brodt ED, Brodke DS, et al. Use of autologous stem cells in lumbar spinal fusion: a systematic review of current clinical evidence. Global Spine J. 2021. Unconcentrated aspirate did not improve fusion in three comparative studies, whereas the Hart randomised trial of concentrated aspirate with allograft chips gave computed-tomography fusion of 80% versus 40% at 24 months (relative risk 2.0, 95% CI 1.3 to 3.0; p = 0.01) and radiographic fusion of 35% versus 10% (p = 0.01); in revision fusion aspirate plus allograft achieved 78% versus 100% for autograft or recombinant bone morphogenetic protein 2 (p = 0.005). 
133. Cole BJ, Kaiser JT, Wagner KR, Sivasundaram L, Otte RS, Tauro TM, et al. Prospective randomised trial of biologic augmentation with bone marrow aspirate concentrate in patients undergoing arthroscopic rotator cuff repair. Am J Sports Med. 2023;51(5):1234–42. Ninety-one patients with isolated 1 to 3 cm supraspinatus tears were randomised to concentrate or sham incision; retear on 1-year magnetic resonance imaging was 57% in controls versus 18% with concentrate (p < 0.001), yet treatment failure and all functional indices were equivalent at 2 years. 
134. Park JY, Ng Hing Cheung JA, Todorov D, Park SY, Lim H, Shin E, et al. Biological augmentation of anterior cruciate ligament reconstruction with bone marrow aspirate concentrate: a systematic review and meta-analysis of randomised controlled trials. Int Orthop. 2025;49(1):35–43. Five randomised trials with 221 patients gave International Knee Documentation Committee mean differences of 2.56 (95% CI -0.19 to 5.32) at 12 months and 5.34 (0.21 to 10.46) at 24 months, judged by the authors to be below clinical significance; three of five trials were at high risk of bias. 
135. Whitney KE, Briggs KK, Chamness C, Bolia IK, Huard J, Philippon MJ, et al. Bone marrow concentrate injection treatment improves short-term outcomes in symptomatic hip osteoarthritis patients: a pilot study. Orthop J Sports Med. 2020;8(12):2325967120966162. In 18 hips of 16 patients, numeric pain at rest fell from 5 to 1 (p < 0.001), Western Ontario and McMaster index from 31 to 16 (p = 0.006) and modified Harris hip score rose from 63 to 80 (p = 0.004), with 2 of 18 hips converting to arthroplasty. 
136. Lee MS, et al. Cost-effectiveness of bone marrow aspirate concentrate augmentation of arthroscopic acetabular labral repair. ISAKOS 2025 abstract 20403. Among 358 patients under 50 years with at least two years of follow-up, 124 received bone marrow aspirate concentrate at an all-inclusive out-of-pocket cost of US$10,000; quality-adjusted life years were 6.162 versus 5.929, giving a gain of 0.233 and an incremental cost-effectiveness ratio of US$42,935 per quality-adjusted life year. 
137. Gobbi A, Karnatzikos G, Scotti C, Mahajan V, Mazzucco L, Grigolo B. One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: results at 2-year follow-up. Cartilage. 2011;2(3):286–99. Fifteen patients with grade 4 lesions averaging 9.2 cm2 received 60 mL of aspirate concentrated four- to six-fold (3904 plus or minus 1232 colony-forming units per mL) under a collagen matrix; visual analogue score fell from 5.1 to 0.7 (p = 0.001) and complete defect filling was seen in 12 of 15 knees. 
138. Whyte GP, Bizzoco L, Gobbi A. One-step cartilage repair of full-thickness knee chondral lesions using a hyaluronic acid-based scaffold embedded with bone marrow aspirate concentrate: long-term outcomes after mean follow-up duration of 14 years. Am J Sports Med. 2024;52(14). Twenty-six patients with a median lesion of 6.6 cm2 were followed a mean 14.0 years; median visual analogue score fell from 5.0 to 0.6 (p < 0.001) with three treatment failures. 
139. Ow ZGW, Cheang HLX, Koh JH, Koh JZE, Lim KKL, Wang D, et al. Does the choice of acellular scaffold and augmentation with bone marrow aspirate concentrate affect short-term outcomes in cartilage repair? A systematic review and meta-analysis. Am J Sports Med. 2023. Concentrate augmentation improved visual analogue scores for single-layered scaffolds (weighted mean difference -4.88, 95% CI -5.38 to -4.37, versus -4.08 without; p = 0.01) and reduced incomplete defect filling, but all significant improvements fell below their respective minimal clinically important differences. 
140. Hede K, Christensen BB, Olesen ML, et al. Combined bone marrow aspirate and platelet-rich plasma for cartilage repair: two-year clinical results. Cartilage. 2021;13(1_suppl):937S–47S. In 10 patients, biopsy histology showed 58% fibrous tissue and 40% fibrocartilage, indicating that repair tissue was predominantly not hyaline.  https://pubmed.ncbi.nlm.nih.gov/31538811/
141. Lind M, et al. Bone marrow aspirate concentrate on a hyaluronic acid scaffold with intra-articular platelet-rich plasma for cartilage lesions in 165 patients. Cartilage. 2026. Outcomes were excellent in 50%, good in 28% and poor in 22%, with a mean Magnetic Resonance Observation of Cartilage Repair Tissue 2.0 score of 71
142. Rodas G, Soler-Rich R, Rius-Tarruella J, Alomar X, Balius R, Orozco L, et al. Effect of autologous expanded bone marrow mesenchymal stem cells or leucocyte-poor platelet-rich plasma in chronic patellar tendinopathy with gap greater than 3 mm: preliminary outcomes after 6 months of a double-blind randomised prospective study. Am J Sports Med. 2021. Twenty athletes received 20 x 10^6 expanded marrow cells or two platelet injections; the Victorian Institute of Sport Assessment patellar score improved in both arms without between-group difference (p = 0.6776), while only the cell arm reduced the intratendinous gap area from 15.06 to 3.38 mm2 (between-group p = 0.0159) and improved the composite magnetic resonance score (between-group p = 0.0041). 
143. de Girolamo L, Filardo G, Abat F, Barfod KW, Bastos R, Cugat R, et al.; ESSKA-ORBIT Group. The use of injectable orthobiologics for knee osteoarthritis: a formal ESSKA-ORBIT consensus. Part 2, cell-based therapy. Knee Surg Sports Traumatol Arthrosc. 2025;33(11):4079–95. Twenty-seven statements averaged 8.2 plus or minus 0.3 of 9; point-of-care cell therapy is supported as a treatment option (Grade B) but not as first-line, platelet-rich plasma is recommended first and cell therapy second (Grade D), there is no sufficient direct evidence of disease modification (Grade C), double-spin concentrate is recommended for knee osteoarthritis (Grade D) and harvest should use multiple punctures of 2 to 5 mL with a 10 mL syringe (Grade C). 
144. Scoping review of cell-based therapy for ankle osteoarthritis and osteochondral lesions. Bioengineering (Basel). 2026;13(7):843. In nine of 11 included studies cells were co-administered with a surgical procedure, making the independent cell effect uninterpretable. 
145. Louwerens JKG, van den Bekerom MPJ, van Royen BJ, Eygendaal D, van Noort A, Sierevelt IN. Quantifying the minimal and substantial clinical benefit of the Constant-Murley score and the Disabilities of the Arm, Shoulder and Hand score in patients with calcific tendinitis of the rotator cuff. JSES Int. 2020;4(3):606–11. The minimal clinically important difference was 9.8 points (95% CI 3.7 to 15.9) for the Constant-Murley score and -8.2 for the Disabilities of the Arm, Shoulder and Hand score. 
146. Pettine KA, Suzuki RK, Sand TT, Murphy MB. Autologous bone marrow concentrate intradiscal injection for the treatment of degenerative disc disease with three-year follow-up. Int Orthop. 2017;41(10):2097–103. Twenty-six fusion candidates received 2 mL of concentrate into the nucleus pulposus; 20 avoided surgery at 36 months with Oswestry index falling from 56.7 to 17.5 and visual analogue score from 82.1 to 21.9, and patients receiving more than 2000 colony-forming units and 2 million CD34-positive cells per mL improved more. 
147. Levi D, Tyszko S, Horn S, Pham N, Levin J. Bone marrow concentrate intradiscal injection for chronic discogenic low back pain: a double-blind randomised sham-controlled trial. Interv Pain Med. 2025;4(3):100611. Among 63 patients, at least 50% pain relief was achieved by 40% of concentrate and 33% of sham patients at 3 months and 44% versus 56% at 12 months, with no significant difference at any timepoint; the authors concluded that intradiscal concentrate was equivalent to a sham procedure. 
148. El-Kadiry AE, Lumbao C, Rafei M, Shammaa R. Autologous BMAC therapy improves spinal degenerative joint disease in lower back pain patients. BMC Musculoskelet Disord. 2022;23(1):23. In a retrospective comparison, bone marrow aspirate concentrate outperformed platelet-rich plasma on visual analogue scale (29.38% improvement, p < 0.002), Knee Injury and Osteoarthritis Outcome Score (53.89%, p < 0.01) and Western Ontario and McMaster Universities Osteoarthritis Index (51.71%, p < 0.011). 
149. Herger N, Bermudez-Lekerika P, Farshad M, et al. Should degenerated intervertebral discs of patients with Modic type 1 changes be treated with mesenchymal stem cells? Stem Cell Res Ther. 2024;15(1):65. Pro-inflammatory cytokine priming and three-dimensional culture both enhanced bone marrow mesenchymal stromal cell T-cell suppression, but the effect faded when cells returned to standard two-dimensional culture. 
150. Abu Salem M, et al. Subchondral injections in knee osteoarthritis: a systematic review of 24 studies and 1,109 patients. Cartilage. 2026. Conversion to total knee arthroplasty after calcium phosphate injection ranged from 1.3% to 45%, and cell-based subchondral treatment showed the best long-term profile. 
151. Di Matteo B, Polignano A, Onorato F, et al. Knee intraosseous injections: a systematic review of clinical evidence of different treatment alternatives. Cartilage. 2021;13(1_suppl):1165S–77S. Of 12 studies and 459 patients receiving intraosseous treatment, only two used bone marrow concentrate. 
152. Sanchez Santiuste M, et al. Intraosseous plus intra-articular plasma rich in growth factors versus intra-articular treatment alone in advanced knee osteoarthritis: a randomised controlled trial. J Clin Med. 2025;14(22):8075. Among 86 patients with Kellgren-Lawrence grade III–IV disease, the intraosseous arm was superior on nearly all Knee Injury and Osteoarthritis Outcome Score and Western Ontario and McMaster Universities Osteoarthritis Index domains at 3, 6 and 12 months (p < 0.05). 
153. Barman A, Prakash S, Sahoo J, Mukherjee S, Maiti R, Roy SS. Single intra-articular injection with or without intraosseous injection of platelet-rich plasma in knee osteoarthritis: a randomised trial. Injury. 2022;53(3):1247–53. The visual analogue scale difference between combined intraosseous plus intra-articular and intra-articular alone was not significant at six months (p = 0.422). 
154. ClinicalTrials.gov identifier NCT05517434. Autologous bone marrow aspirate versus saline for knee osteoarthritis: a quadruple-blind randomised phase 2/3 trial of 148 participants, University Health Network, Toronto. 
155. ClinicalTrials.gov identifier NCT06311513. Concentrated bone marrow aspirate versus sham incision in revision anterior cruciate ligament reconstruction: randomised phase 4 trial of 40 participants, Hospital for Special Surgery. 
156. ClinicalTrials.gov identifier NCT06040957. Bone marrow versus adipose tissue for knee osteoarthritis: randomised trial of 204 participants, Istituto Ortopedico Rizzoli. 
157. Liew A, Bhattacharya V, Shaw J, Stansby G. Cell therapy for critical limb ischemia: a meta-analysis of randomized controlled trials. Angiology. 2016;67(5):444–55. Across 16 randomised trials, cell therapy reduced amputation (odds ratio 0.54, 95% confidence interval 0.34–0.87), but the effect was null when analysis was restricted to placebo-controlled trials. 
158. Peeters Weem SM, Teraa M, de Borst GJ, Verhaar MC, Moll FL. Bone marrow derived cell therapy in critical limb ischemia: a meta-analysis of randomized placebo controlled trials. Eur J Vasc Endovasc Surg. 2015;50(6):775–83. Ten placebo-controlled trials gave a risk ratio for amputation of 0.91 (95% confidence interval 0.65–1.27), with mean differences of 0.11 for ankle-brachial index and 11.88 mmHg for transcutaneous oxygen tension.
159. Abdul Wahid SF, Ismail NA, Wan Jamaludin WF, et al. Autologous cells derived from different sources and administered using different regimens for no-option critical lower limb ischaemia patients. Cochrane Database Syst Rev. 2018;8:CD010747. The review found no evidence supporting routine autologous cell therapy in no-option critical limb ischaemia. 
160. Afzal MR, Samanta A, Shah ZI, et al. Adult bone marrow cell therapy for ischemic heart disease: evidence and insights from randomized controlled trials. Circ Res. 2015;117(6):558–75. Pooled analysis of 48 randomised trials showed an improvement in left ventricular ejection fraction of 2.92% (95% confidence interval 1.91–3.92). 
161. Delewi R, Andriessen A, Tijssen JG, Zijlstra F, Piek JJ, Hirsch A. Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis. Eur Heart J. 2014;35(15):989–98. Left ventricular ejection fraction improved by 2.55% overall and by 5.30% in patients with baseline ejection fraction below 40%. 
162. Powell RJ, Marston WA, Berceli SA, et al. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial and the MOBILE experience with bone marrow aspirate concentrate. Among 152 patients treated with a point-of-care marrow concentrate, one-year amputation-free survival was 80%. 
163. Fisher SA, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2016;12:CD007888. Across 38 randomised trials, long-term mortality risk ratio was 0.42 (95% confidence interval 0.21–0.87) on low-quality evidence, while left ventricular ejection fraction showed a non-significant mean difference of −1.60.
164. Mathur A, Fernandez-Aviles F, Bartunek J, et al. The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial. Eur Heart J. 2020;41(38):3702–10. In 375 patients, two-year all-cause mortality was 3.26% with cell therapy versus 3.82% with control, a non-significant difference. 
165. Bartunek J, Terzic A, Davison BA, et al. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the CHART-1 randomised controlled trial. Eur Heart J. 2017;38(9):648–60. The primary hierarchical composite was neutral (Finkelstein-Schoenfeld 0.52, p = 0.51), with benefit confined to a subgroup defined by baseline left ventricular end-diastolic volume. 
166. Zhang Y, et al. Efficacy and safety of stem cell therapy for diabetic foot ulcer: a systematic review and meta-analysis of randomised controlled trials. Front Endocrinol (Lausanne). 2026. Thirty-two randomised trials with 2,059 participants gave an odds ratio for complete healing of 4.64 (95% confidence interval 3.11–6.90) and for amputation of 0.29; the bone-marrow mesenchymal stromal cell subgroup odds ratio was 8.33. No dedicated trial of bone marrow aspirate concentrate in diabetic foot ulcer was identified. 
167. Mesenchymal stromal cell therapy for liver cirrhosis. Cochrane Database Syst Rev. 2025. Across 12 trials, mortality risk ratio was 0.52 (95% confidence interval 0.24–1.11) on very low certainty evidence.  https://pubmed.ncbi.nlm.nih.gov/40371762/
168. Uccelli A, Laroni A, Ali R, et al. Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): a phase 2, randomised, double-blind crossover trial. Lancet Neurol. 2021;20(11):917–29. In 144 patients the gadolinium-enhancing lesion rate ratio was 0.94 (95% confidence interval 0.58–1.50, p = 0.78), a definitively negative result. 
169. Panes J, et al. Long-term efficacy and safety of darvadstrocel for complex perianal fistulas in Crohn disease: the ADMIRE-CD II randomised trial. Gastroenterology. 2026. In 568 patients the treatment difference for combined remission was 2.4% (95% confidence interval −5.8 to 10.6, p = 0.571); the product was subsequently withdrawn from the European market. 
170. European Medicines Agency. Alofisel (darvadstrocel): withdrawal of the marketing authorisation in the European Union, 13 December 2024. Marketing authorisation had been granted on 23 March 2018. 
171. Pasquali PJ, Teixeira ML, de Oliveira TA, de Macedo LG, Aloise AC, Pelegrine AA. Maxillary sinus augmentation combining bio-oss with the bone marrow aspirate concentrate: a histomorphometric study in humans. Int J Biomater. 2015;2015:121286. Vital mineralised tissue was 55.15 ± 20.91% with bone marrow aspirate concentrate plus anorganic bovine bone versus 27.30 ± 5.55% in controls (p < 0.05). 
172. Comparison of single and double bone marrow aspirate concentrate concentrations in maxillary sinus augmentation. Int J Oral Maxillofac Implants. 2016;31(1):216–22. Vital mineralised tissue was 38.44 ± 12.34% with single concentration, 34.63 ± 9.84% with double concentration and 27.30 ± 5.55% in controls, with no significant dose effect.  https://pubmed.ncbi.nlm.nih.gov/26800181/
173. Shanbhag S, Pandis N, Mustafa K, Nyengaard JR, Stavropoulos A. Cell therapy for orofacial bone regeneration: a systematic review and meta-analysis. J Clin Periodontol. 2019;46(Suppl 21):162–82. Across 47 clinical and 57 preclinical studies, whole bone marrow with a scaffold was superior to scaffold alone in sinus and ridge augmentation and comparable to autograft in cleft repair. 
174. Tang Y, et al. Efficacy of mesenchymal stem cell therapy for stroke: a meta-analysis of randomised controlled trials. Across six randomised trials, the three-month National Institutes of Health Stroke Scale standardised mean difference was −0.34 (95% confidence interval −0.57 to −0.11, p = 0.004), with a null result at six months. 
175. Siqueira RC, Messias A, Messias K, et al. Quality of life in patients with retinitis pigmentosa submitted to intravitreal use of bone marrow-derived stem cells. Stem Cell Res Ther. 2015;6:29. Quality-of-life gains observed at three months were no longer present at 12 months.
176. Kebriaei P, Hayes J, Daly A, et al. A phase 3 randomized study of remestemcel-L versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2020;26(5):835–44. In 260 patients durable complete response was 35% versus 30% (p = 0.42), with benefit confined to the grade C/D subgroup (58% versus 37%, p = 0.03). 
177. Kurtzberg J, Prockop S, Chaudhury S, et al. Study 275: updated expanded access program for remestemcel-L in steroid-refractory acute graft-versus-host disease in children. Biol Blood Marrow Transplant. 2020;26(5):845–54. In 54 children, day-28 overall response was 70.4% against a protocol-specified control rate of 45% (p = 0.0003), with day-100 survival of 74.1%. 
178. United States Food and Drug Administration. FDA approves first mesenchymal stromal cell therapy to treat steroid-refractory acute graft-versus-host disease. Press announcement, 18 December 2024. Ryoncil (remestemcel-L-rknd), an allogeneic bone marrow-derived mesenchymal stromal cell product, was approved for children aged two months and older.  https://www.fda.gov/news-events/press-announcements/fda-approves-first-mesenchymal-stromal-cell-therapy-treat-steroid-refractory-acute-graft-versus-host
179. Lechanteur C, Briquet A, Giet O, Delloye O, Baudoux E, Beguin Y. Clinical-scale expansion of mesenchymal stromal cells: a large banking experience. J Transl Med. 2016;14(1):145. Sixty-eight clinical-grade cultures from 59 validated donors produced a mean final yield of 886 million cells per culture and 464 cryopreserved aliquots at a mean 132.8 million cells per bag. 
180. Oja S, Kaartinen T, Ahti M, Korhonen M, Laitinen A, Nystedt J. The utilization of freezing steps in mesenchymal stromal cell manufacturing: potential impact on quality and cell functionality attributes. Front Immunol. 2019;10:1627. A validated single-freeze protocol preserved viability, phenotype and differentiation but thawed cells showed an approximately 50% reduction in in-vitro immunosuppressive capacity; four or more freezing steps may induce earlier senescence. 
181. Wiese DM, Wood CA, Ford BN, Braid LR. Cytokine activation reveals tissue-imprinted gene profiles of mesenchymal stromal cells. Proc Natl Acad Sci U S A. 2021;118(35). Interferon-gamma licensing generated heterogeneous rather than uniform mesenchymal stromal cell responses, a central manufacturing problem. 
182. Jakl V, Popp T, Haupt J, et al. Effect of different preparation methods on the properties of small extracellular vesicles from bone marrow mesenchymal stromal cells. Front Bioeng Biotechnol. 2023;11:1107055. Isolation method produced considerable variability in vesicle quantity, purity and characteristics; cross-flow filtration with ultracentrifugation approximated the differential-centrifugation standard whereas polyethylene glycol precipitation did not. 
183. Morata-Tarifa C, Macias-Sanchez MDM, Gutierrez-Pizarraya A, Sanchez-Pernaute R. Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease: a meta-analysis. Stem Cell Res Ther. 2020;11(1):64. Prophylaxis increased overall survival by 17% (95% confidence interval 1.02–1.33) and reduced grade IV acute disease (risk ratio 0.22, 95% confidence interval 0.06–0.81); in acute disease, survival correlated with cell dose (p = 0.0214). 
184. Fernandez-Garza LE, Barrera-Barrera SA, Barrera-Saldana HA. Mesenchymal stem cell therapies approved by regulatory agencies around the world. Pharmaceuticals (Basel). 2023;16(9):1334. Twelve mesenchymal stromal cell products had been approved worldwide, nine of them in Asia and the Republic of Korea leading, against 1,120 registered mesenchymal stromal cell clinical trials as of April 2023. 
185. Patel AN, Henry TD, Quyyumi AA, et al. Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial (ixCELL-DCM). Lancet. 2016;387(10036):2412–21. The composite of death, cardiovascular hospitalisation and unplanned clinic visits was reduced with a risk ratio of 0.63 (95% confidence interval 0.42–0.97, p = 0.0344). 
186. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells Dev. 2020;29(12):747–54. In 24 patients, a single 15 mL intravenous dose was followed by an average 192% rise in the ratio of arterial oxygen tension to inspired oxygen fraction (p < 0.001), with 83% survival and no adverse events within 72 hours.
187. Lightner AL, Sengupta V, Qian S, et al. Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for the treatment of respiratory failure from COVID-19: a randomized, placebo-controlled dosing clinical trial. Chest. 2023;164(6):1444–53. Among 102 patients the primary endpoint of 60-day all-cause mortality was not met (p = 0.1343); post-hoc analysis of the 15 mL arm gave a relative risk of 0.385 (95% confidence interval 0.159–0.931, p = 0.0340). 
188. Bain BJ. Bone marrow biopsy morbidity and mortality. Br J Haematol. 2003;121(6):949–51. Twenty-six adverse events including one death among an estimated 54,890 biopsies; haemorrhage in 14 patients, transfusion required in 6. 
189. Bain BJ. Morbidity associated with bone marrow aspiration and trephine biopsy: a review of UK data for 2004. Haematologica. 2006;91(9):1293–94. Fifteen adverse events among 20,323 procedures, mainly haemorrhagic. 
190. Lee SH, Erber WN, Porwit A, Tomonaga M, Peterson LC; International Council for Standardization in Haematology. ICSH guidelines for the standardization of bone marrow specimens and reports. Int J Lab Hematol. 2008;30(5):349–64. Progressive dilution with peripheral blood accompanies increasing aspirate volume; a 10- or 20-mL syringe is required for adequate negative pressure; sternal aspiration should be performed only by experienced operators aware of the risk of cardiac tamponade. 
191. Sanabria-de la Torre R, Quinones-Vico MI, Fernandez-Gonzalez A, et al. Alloreactive immune response associated to human mesenchymal stromal cells treatment: a systematic review. J Clin Med. 2021;10(13):2991. Among 356 patients receiving allogeneic cells, a mean 11.51% developed donor-specific antibodies, without correlation to safety, tolerability, dose number or degree of human leucocyte antigen mismatch. 
192. Patino JA, et al. Morbidity and mortality associated with performing bone marrow aspiration and biopsy. Int Phys Med Rehab J. Among 1,252 procedures in 914 patients there were 77 complications (6.15%), of which all reported pain and only seven were non-pain events (0.53%); major bleeding occurred in three (0.2%), infection in two (0.15%), and one patient died of retroperitoneal haematoma (0.07%). The same report cites a British Society of Haematology national survey of 54,890 biopsies with 26 adverse events (0.047%) and one death. 
193. Elattar O, et al. Donor-site morbidity after iliac crest bone marrow aspirate concentrate harvest for foot and ankle arthrodesis. Foot Ankle Int. 2021. Among 55 patients, 50% reported immediate postoperative harvest-site pain, two had non-limiting pain persisting to six months, and three had persistent complications or dissatisfaction beyond six months; good-to-excellent results were achieved in 52 of 55 (94.5%). 
194. Fucaloro SP, et al. Complication rates of bone marrow aspirate concentrate injections versus other injectable therapies for knee osteoarthritis: a systematic review and meta-analysis. J Orthop. 2025;62:36–42. Across six randomised trials, complications occurred in 140 of 334 bone marrow aspirate concentrate patients (41.91%) versus 217 of 526 comparators (41.25%), p = 0.85, absolute risk increase 0.66%, number needed to harm 152; effusion occurred in 18.26% and infection in none.
195. Complications following biologic therapeutic injections: a multicenter case series. Arthroscopy. 2021. Among 14 patients from six United States institutions, seven (50.0%) had culture- or pathology-confirmed septic arthritis and six (42.9%) a suspected sterile inflammatory response; mean time from injection to presentation was 8.9 days, the seven infections required a mean 3.6 operations, and 12 of 14 index injections had been performed at outside clinics. 
196. Complications of stem cell-based injections for knee osteoarthritis: a systematic review. 2024. Of 427 studies screened, 48 were included with 1,924 patients; the overall transient adverse-event rate was 12.3%, rising to 51.7% for umbilical cord-derived products and 29.5% for cultured adipose-derived cells, with no infection, fat embolism, sepsis, neoplasm, embolism or death across the dataset. 
197. Prodromos C, Rumschlag T, Finkle S. Mesenchymal stem cell treatment does not result in tumor formation: a systematic review. Among 217 articles and 4,796 mesenchymal stromal cell-treated patients with a mean follow-up of 13.92 months, 12 malignancies (0.25%) were reported versus six in controls
198. Barkholt L, Flory E, Jekerle V, et al. Risk of tumorigenicity in mesenchymal stromal cell-based therapies: bridging scientific observations and regulatory viewpoints. Extensive in-vitro expansion increases the risk that genetically abnormal cells arise and are propagated; chromosomal abnormalities exist at early passages and can be clonally propagated, yet there are no reports of malignant transformation in clinically used mesenchymal stromal cells and the tumourigenic potential remains unresolved. 
199. Wang Y, Yi H, Song Y. The safety of mesenchymal stromal cell transplantation: a 15-year meta-analysis. Stem Cell Res Ther. 2021. Across 62 trials and 3,546 participants, transient fever odds ratio was 3.65 (95% confidence interval 2.05–6.49) and administration-site adverse events 1.98 (1.01–3.87), while death (0.99) and infection (1.03) were unchanged; no pooled malignancy estimate was possible and the authors found no direct evidence of tumourigenicity. 
200. United States Food and Drug Administration, Center for Biologics Evaluation and Research. Same surgical procedure exception under 21 CFR 1271.15(b): questions and answers regarding the scope of the exception. Guidance for industry, November 2017. Minimally manipulated bone marrow for homologous use, not combined with another article, is not considered a human cell, tissue or cellular and tissue-based product under 21 CFR 1271.3(d); permitted processing under the exception is limited to rinsing, cleansing, sizing and shaping, with centrifugation or filtration allowed only to remove debris. 
201. United States Food and Drug Administration. Questions and answers regarding the end of the compliance and enforcement policy for certain human cells, tissues, or cellular or tissue-based products. Enforcement discretion regarding investigational new drug and premarket approval requirements ended on 31 May 2021; every establishment manufacturing products regulated as drugs or biologics is expected to hold an approved biologics licence application or an investigational new drug application in effect. 
202. United States Food and Drug Administration, Center for Biologics Evaluation and Research. Enforcement actions: biologics internet surveillance and other. The listing includes 18 untitled-letter entries plus one affiliate letter covering 19 named stem-cell or regenerative-medicine firms between 2018 and 2023. 
203. United States Food and Drug Administration. Important patient and consumer information about regenerative medicine therapies. The agency lists ectopic tissue formation, tumour formation, immune reactions and cross-contamination among the risks of unapproved products and states that it has received reports of blindness, tumour formation and infections. 
204. United States v. US Stem Cell Clinic, LLC, 998 F.3d 1302 (11th Cir. 2021). The Eleventh Circuit affirmed a permanent injunction after the district court held on 3 June 2019 that the clinic's stromal vascular fraction product was an adulterated and misbranded drug. 
205. AABB. Supreme Court declines stem cell case, upholding FDA oversight of cell therapies, 15 October 2025. The Ninth Circuit's September 2024 ruling reversed the district court and rejected the argument that same-day stromal vascular fraction treatments qualify for the same-surgical-procedure exception; the Supreme Court's refusal of certiorari left that holding in place. 
206. Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous adipose tissue-derived stem cells for age-related macular degeneration. N Engl J Med. 2017;376(11):1047–53. Three patients with pre-injection acuity of 20/30 to 20/200 declined to 20/200 to no light perception at one year, with retinal detachment, vitreous haemorrhage and lens dislocation. 
207. Perkins KM, Spoto S, Rankin DA, et al. Notes from the field: infections after receipt of bacterially contaminated umbilical cord blood products for non-hematopoietic indications. MMWR Morb Mortal Wkly Rep. 2018;67(50):1397–9. Twelve patients across three states were hospitalised with bloodstream infections, joint infections and epidural abscesses caused by Enterobacter cloacae, Citrobacter freundii, Escherichia coli, Enterococcus faecalis and Proteus mirabilis; 11 of 12 had been treated for pain or orthopaedic conditions. 
208. Berkowitz AL, Miller MB, Mir SA, et al. Glioproliferative lesion of the spinal cord as a complication of stem-cell tourism. N Engl J Med. 2016;375(2):196–8. A 66-year-old man developed paraplegia from an intradural mass after intrathecal infusions abroad; short tandem repeat fingerprinting showed the lesion was composed predominantly of non-host cells, and a 309-gene panel found no cancer-associated aberrations. 
209. Turner LG. ISSCR's guidelines for stem cell research and clinical translation in the context of unproven stem cell-based interventions. Cell Stem Cell. 2021. As of 31 March 2021, 1,480 United States businesses operated 2,754 clinics marketing purported stem cell interventions, up more than fourfold from 351 businesses and 570 clinics in 2016; 1,262 (85.27%) advertised treatment of painful symptoms and 689 (46.55%) orthopaedic conditions, and among the 56 businesses (3.78%) publishing prices the mean was US$5,118 and the median US$4,000 (range US$1,200–28,000). 
210. Piuzzi NS, Ng M, Chughtai M, et al. The stem-cell market for the treatment of knee osteoarthritis: a patient perspective. J Knee Surg. Across 65 centres the mean price was US$5,156 (standard deviation US$2,446; 95% confidence interval US$4,550–5,762) with a range of US$1,150–12,000, and marketed efficacy averaged 82.2% (range 55–100%). 
211. United States Federal Trade Commission. Stem Cell Institute of America co-founders and companies banned from marketing stem cell treatments and ordered to pay more than US$5.1 million, January 2025. Summary judgment was granted in March 2024 on all counts, with relief orders issued on 26 December 2024 comprising US$3,310,146 in refunds and US$1,845,000 in civil penalties and a permanent ban on marketing any regenerative medicine treatment. 
212. United States Federal Trade Commission. FTC stops deceptive health claims by a stem cell therapy clinic, 18 October 2018. The defendants earned at least US$3.31 million between 2014 and 2017 advertising that amniotic stem cell therapy could treat Parkinson disease, autism, macular degeneration, cerebral palsy, multiple sclerosis and heart attacks; the settlement imposed a partially suspended US$3.31 million judgment and prohibited unsupported claims including for osteoarthritis
213. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. OJ L 324, 10 December 2007, pp. 121–137. 
214. Regulation (EU) 2024/1938 of the European Parliament and of the Council of 13 June 2024 on standards of quality and safety for substances of human origin intended for human application. OJ L, 17 July 2024. General application begins 7 August 2027; the Regulation does not apply to autologous substances that are neither processed nor stored before application, but does apply to bedside processing using devices whose quality, safety and effectiveness were not demonstrated for that specific purpose as part of CE marking. 
215. Medicines and Healthcare products Regulatory Agency (United Kingdom). Advanced therapy medicinal products: regulation and licensing in the UK. Supply of unlicensed advanced therapy medicinal products is possible only through the hospital exemption for non-routine preparation or the specials scheme, and a manufacturer's licence from the agency is required for either route; no minimal-manipulation exemption is published. 
216. Health Canada. Policy position paper: autologous cell therapy products. Autologous cell therapy products meet the definition of a drug under the Food and Drugs Act and require a new drug submission or a clinical trial application under Division 5, Part C of the Food and Drug Regulations; the only exception is minimally manipulated lympho-haematopoietic cells for homologous use in transplantation, and a medical device licence for processing equipment does not constitute review of the cell therapy output. 
217. Therapeutic Goods Administration (Australia). Exempt autologous human cells and tissues, version 1.0, July 2018. Exemption under Schedules 5 and 7 of the Therapeutic Goods Regulations requires that the product be collected from a patient under the clinical care of a registered medical or dental practitioner, manufactured and used by or under the supervision of that practitioner, for a single indication in a single clinical procedure, and minimally manipulated for homologous use; exempt products must not be advertised to consumers and criminal penalties may apply. 
218. Regulatory framework for regenerative medicine in Japan under the Act on the Safety of Regenerative Medicine. Implemented 25 November 2014, the Act assigns autologous mesenchymal stromal cells and autologous somatic cells not for homologous use to Class II, requiring a provision plan reviewed by an accredited Certified Committee for Regenerative Medicine and notified to the Minister of Health, Labour and Welfare; an amendment promulgated 14 June 2024 extends the Act to gene therapy, genome editing and messenger RNA products, while exosomes remain outside its scope. 
219. Conselho Federal de Medicina (Brazil). Resolucao CFM no 2.464, de 2 de julho de 2026. Diario Oficial da Uniao, 15 July 2026, Edicao 131, Secao 1, p. 70. Platelet-rich plasma is regulated as an adjuvant medical procedure for knee osteoarthritis, lumbar discopathy, lateral elbow epicondylitis and meniscal repair; Article 5 prohibits adding medicines, biologically active substances, cell products, stem cells, bone marrow concentrate, stromal vascular fraction, microfragmented fat or recombinant growth factors to platelet-rich plasma outside formally approved clinical research, and Article 13 prohibits promises of cure, guarantees of result, assured tissue regeneration or claims of substitution for indicated surgery. The resolution revokes Resolucao CFM 2.128/2015. 
220. Conselho Federal de Medicina (Brazil). Parecer CFM no 43/2016, 28 October 2016. The use of bone marrow aspirate for the treatment of orthopaedic lesions is an experimental procedure and may be performed only within research protocols approved under the national research ethics system. 
221. Conselho Federal de Medicina (Brazil). Resolucao CFM no 2.336, de 13 de julho de 2023, on medical advertising and publicity. Diario Oficial da Uniao, 13 September 2023, Edicao 175, Secao 1, p. 312. Article 11 prohibits attributing privileged capacity to equipment, advertising equipment or medicines without national health agency registration, promoting methods or techniques not recognised by the Council, and guaranteeing, promising or insinuating good treatment results; Paragraph 5 defines untruthful content as advertising of revolutionary or miraculous practices or new procedures not approved for medical use by the Council. 
222. Agencia Nacional de Vigilancia Sanitaria (Brazil). Resolucao da Diretoria Colegiada RDC no 505, de 27 de maio de 2021, on the registration of advanced therapy products. Class I comprises minimally manipulated products with non-homologous function and Class II extensive manipulation, tissue engineering and gene therapy; the resolution entered into force on 1 July 2021. 
223. World Anti-Doping Agency. The 2026 Prohibited List, international standard, effective 1 January 2026. Section S2.3 prohibits growth factors and growth factor modulators at all times, including platelet-derived growth factor, insulin-like growth factor 1, vascular endothelial growth factor and thymosin-beta 4; M1 prohibits reintroduction of blood into the circulatory system; M2.2 prohibits intravenous infusions or injections exceeding 100 mL per 12-hour period outside hospital treatment; and M3.2 prohibits the use of normal or genetically modified cells or cell components. 
224. World Anti-Doping Agency. Athlete and athlete support personnel guide to the 2026 Prohibited List. The guide confirms that the use of normal or genetically modified cells or cell components, including nuclei, mitochondria and ribosomes, is banned, describing an expanded scope encompassing the complete cell structure and key functional organelles. 
225. United States Anti-Doping Agency. Orthobiologics: what athletes need to know about platelet-rich plasma. The agency states that platelet-rich plasma is not prohibited under World Anti-Doping Agency regulations, that it becomes prohibited if altered to enhance performance, that the only expected result is restoration of pre-injury function, and that individual growth factors remain prohibited when given separately as purified substances; bone marrow aspirate concentrate is not addressed. 
226. Global Market Insights. Bone marrow aspirate concentrates market size, share and forecast. The market was valued at US$172.8 million in 2023, with North America at US$70 million and hospitals and clinics holding a 35.3% share, and is projected to grow at more than 5.4% annually to 2032.
227. Strategic Market Research. Bone marrow aspirate concentrates market report. The market is valued at US$2.4 billion in 2024 and projected to reach US$5.13 billion by 2030 at a compound annual growth rate of 13.5%, with aspiration kits holding a 60% share. 
228. Grand View Research. Orthobiologics market size, share and trends analysis report. The global orthobiologics market was US$6.77 billion in 2024 and is projected to reach US$10.34 billion by 2033 at a compound annual growth rate of 4.74%, with viscosupplementation the largest product segment at 42.21%, spinal fusion the largest application at 48.29%, and North America 46.03% of the global market. 
229. Blue Cross Blue Shield Association. Medical policy 8.01.52: orthopedic applications of stem cell therapy. Effective 1 April 2026; last revised 23 March 2026. Mesenchymal stem cell therapy is considered investigational for all orthopaedic applications, as are allograft products containing viable stem cells and graft substitutes that must be combined with autologous blood or bone marrow; demineralised bone matrix products designed to be mixed with marrow are cleared through the 510(k) pathway under product code MQV, and transplantation codes 38205 to 38241 are not appropriate for orthopaedic stem cell billing. 
230. Cigna. Coverage policy 0552: stem cell therapy for orthopedic applications, effective 15 December 2025. Stem cell therapy is considered not medically necessary for regeneration or repair of musculoskeletal tissue, joint disease, osteoarthritis of the knee, hip, ankle or shoulder, fracture repair including long-bone nonunion, and osteonecrosis repair; the Medicare table records no national coverage determination and no local coverage determination. 
231. Anthem. Medical policy TRANS.00035: therapeutic use of stem cells, blood and bone marrow products, published 1 July 2026, last reviewed 14 May 2026. Use of bone marrow aspirate concentrate is considered investigational and not medically necessary for all indications, including critical limb ischaemia; mesenchymal stromal cell therapy, autologous bone marrow mononuclear cell therapy and platelet-rich plasma are likewise investigational for all indications. 
232. Aetna. Clinical policy bulletin 0784: blood and adipose tissue derived products for selected indications. Bone marrow-derived mesenchymal stromal cell administration for facet joint injections, avascular necrosis of the shoulder, Crohn disease and osteoarthritis, and bone marrow plasma injection for tendinopathies of the elbow, heel, knee and shoulder, are considered experimental, investigational or unproven
233. Centers for Medicare and Medicaid Services. Local coverage determination L39879: amniotic and placental-derived product injections and/or applications for musculoskeletal indications, non-wound. The determination is a non-coverage policy on the basis that there is insufficient evidence-based literature to support coverage and that Medicare reasonable and necessary requirements have not been met; the current effective period began 12 January 2024. 
234. Onuki TS, Sa KMM, Alves N, de Souza SI, Santos EM, Martimbianco ALC. Methodological quality of systematic reviews on platelet-rich plasma therapy for osteoarthritis: a meta-research study. Rev Bras Ortop (Sao Paulo). 2025;60(1). Of 31 systematic reviews, 26 (83.8%) were of critically low and five (16.13%) of low AMSTAR-2 quality with none moderate or high; only six (19.35%) applied the GRADE approach, 93.5% did not report the funding sources of included trials, and all 31 failed to report reasons for excluding trials. 
235. Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, et al. 2019 American College of Rheumatology and Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip and knee. Arthritis Rheumatol. 2020;72(2):220–33. Stem cell injections and platelet-rich plasma are strongly recommended against in knee and hip osteoarthritis, citing heterogeneity and lack of standardisation, while intra-articular glucocorticoid is strongly recommended
236. Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, et al. OARSI guidelines for the non-surgical management of knee, hip and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27:1578–89. Intra-articular stem cell therapy and platelet-rich plasma were strongly recommended against because the supporting evidence is of extremely low quality and the formulations are not standardised.