Orthopedic Stem Cell Research: A Review
Some doctors and media channels argue that there is very little evidence to support the use of stem cells to treat orthopaedic conditions. However, there are more than 200 studies related to the use of stem cells in treating orthopaedic conditions.
Here, we have listed and compiled all recent significant scientific publications. The list was complied by running various searches on body parts and bone marrow cell types on PubMed. Each title represents a research study and is hyperlinked to the abstract in the U.S. National Library of Medicine.
A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions.
Authors: Centeno CJ, Al-Sayegh H, Freeman MD, Smith J, Murrell WD, Bubnov R.
Publication: Int Orthop. 2016 Aug;40(8):1755-1765. doi: 10.1007/s00264-016-3162-y. Epub 2016 Mar 30.
Study Method: 9 years follow up prospective study.
No. of patients: 2,372
Treatment Method: All patients underwent an MSC-based (mesenchymal stem cell based), percutaneous injection treatment of an orthopaedic condition between December 2005 and September 2014 at one of 18 clinical facilities. Treated areas of the body included the knee, hip, ankle/foot, hand/wrist, elbow, shoulder, and spine.
Conclusion (s): Lowest rate of adverse events was among those patients receiving BMC (bone marrow concentrate) injections alone, but the higher rate of AEs for BMC plus adipose and cultured cells was readily explained by the nature of the therapy or the longer follow-up. There was no clinical evidence to suggest that treatment with MSCs of any type in this study increased the risk of neoplasm (cancer).
Return to Sports After Bone Marrow-Derived Cell Transplantation for Osteochondral Lesions of the Talus (Ankle).
Authors: Vannini F, Cavallo M, Ramponi L, Castagnini F, Massimi S, Giannini S, Buda RE.
Publication: Cartilage. 2017 Jan;8(1):80-87. Epub 2016 Apr 12.
Study Method: Case series, 48 months follow up.
No. of patients: 140
Treatment Method: A "one-step" BMDCT (bone marrow derived cell transplantation) repair of OLT (osteochondral lesion of the talus. All the patients had the cells harvested from the iliac crest, condensed and loaded on a scaffold, and then implanted.
Conclusion (s): "One-step" BMDCT repair of OLT had good clinical results that was durable over time in athletes, permitting a return to sports at pre-injury level in the majority of patients. The preoperative presence of impingement and articular degeneration were the main negative prognostic factors.
A dose response analysis of a specific bone marrow concentrate treatment protocol for knee osteoarthritis.
Publication: BMC Musculoskelet Disord. 2015 Sep 18;16:258. doi: 10.1186/s12891-015-0714-z.
Study Method: Retrospective study.
No. of patients: 373
Treatment Method: Data from an ongoing patient registry was culled to identify 373 patients that received bone marrow concentrate injections for the treatment of 424 osteoarthritic knee joints. The lower and higher cell count groups were defined using a threshold of 4 × 10(8) cells. There were 224 and 185 knee joints treated in the lower (≤4 × 10(8)) and higher (>4 × 10(8)) cell count groups respectively.
Conclusion (s): Improved function and reduced pain was observed in patients treated with a bone marrow concentrate protocol regardless of cellular dose; however, patients receiving a higher concentration of cells reported a better pain outcome in comparison with the lower dose group. These preliminary findings suggest that cell dose may be an important factor governing clinical outcomes in autologous bone marrow concentrate treatment of knee osteoarthritis. Further studies using a larger patient population may help elucidate these findings.
Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): Preclinical and clinical trial in osteoarthritis of the knee joint.
Authors: Gupta PK, Chullikana A, Rengasamy M, Shetty N, Pandey V, Agarwal V, Wagh SY, Vellotare PK, Damodaran D, Viswanathan P, Thej C, Balasubramanian S, Majumdar AS.
Publication: Arthritis Res Ther. 2016 Dec 20;18(1):301.
Study Method: Double blinded controlled trial.
No. of patients: 60
Treatment Method: The in vitro differentiation potential of adult human bone marrow derived, cultured, pooled, allogeneic MSCs (mesenchymal stem cells) injected into knee joint with different doses of cells (25, 50, 75, or 150 million cells) or placebo.
Conclusion (s): Intraarticular administration of Stempeucel was safe, and a trend towards improvement was seen in the 25-million-cell dose group in all subjective parameters Adverse events were predominant in the higher dose groups. Intraarticular administration of Stempeucel is safe. A 25-million cell dose may be the most effective among the doses tested for pain reduction.
Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft.
Authors: Centeno CJ, Pitts J, Al-Sayegh H, Freeman M.
Study Method: Retrospective study. Treatment registry data for patients who underwent BMC procedures with and without an adipose graft were analyzed.
No. of patients: 681
Treatment Method: Autologous bone marrow concentrate (BMC) with and without an adipose graft, for treatment of knee osteoarthritis (OA).
Conclusion(s): BMC (bone marrow concentrate) injections for knee OA showed encouraging outcomes and a low rate of AEs. Addition of an adipose graft to the BMC did not provide a detectible benefit over BMC alone.
Publication: J Bone Joint Surg Am. 2013 Dec 18;95(24):2215-21. doi: 10.2106/JBJS.M.00261.
Study Method: Patients were monitored for cancer incidence from the date of the first operation (1990) until death, or until December 31, 2011. The mean follow-up time was 12.5 years (range, five to twenty-two years).
No. of patients: 1873
Treatment Method: Patients who had received autologous bone marrow-derived stromal progenitor cells to treat orthopaedic lesions.
Conclusion(s): This study found no increased cancer risk in patients after application of autologous cell-based therapy using bone marrow-derived stromal progenitor cells either at the treatment site or elsewhere in the patients after an average follow-up period of 12.5 years.
Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial.
Authors: Koh YG, Kwon OR, Kim YS, Choi YJ, Tak DH.
Publication: Arthroscopy. 2016 Jan;32(1):97-109. doi: 10.1016/j.arthro.2015.09.010. Epub 2015 Nov 14.
Study Method: Unblinded prospective randomised controlled trial
No. of patients: 80
Treatment Method: Compare ADSCs (adipose derived stem cells) with fibrin glue and MFX (microfracture) versus MFX (microfracture) alone for the treatment of cartilage defects in the knee.
Intraarticular injections of HA (hyaluronic acid) with and without PBSC (peripheral blood stem cells).
Authors: Saw KY, Anz A, Siew-Yoke Jee C, Merican S, Ching-Soong Ng R, Roohi SA, Ragavanaidu K.
Publication: Arthroscopy. 2013 Apr;29(4):684-94. doi: 10.1016/j.arthro.2012.12.008. Epub 2013 Feb 4.
Study Method: Randomized, unblinded, controlled study.
No. of patients: 50
Treatment Method: Intra-articular injections of HA with and without PBSC.
Conclusion (s): The total ICRS II (International Cartilage Repair Society Visual Assessment Scale II) histologic scores for the control group averaged 957, and they averaged 1,066 for the intervention group. On evaluation of the MRI morphologic scores, the control group averaged 8.5 and the intervention group averaged 9.9. After arthroscopic subchondral drilling into grade 3 and 4 chondral lesions, postoperative intraarticular injections of autologous PBSC in combination with HA resulted in an improvement of the quality of articular cartilage repair over the same treatment without PBSC (peripheral blood stem cells).
Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: A prospective, randomized controlled clinical trial with 2 years’ follow-up.
Authors: Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH.
Publication: Arthroscopy. 2013 Dec;29(12):2020-8. doi: 10.1016/j.arthro.2013.09.074.
Study Method: Prospective unblinded controlled trial.
No. of patients: 56
Treatment Method: Intraarticular cultured autologous BM-MSCs (bone marrow mesenchymal stem cells) injections in conjunction with MFX and medial opening-wedge HTO (high tibial osteotomy).
Conclusion (s): The effect of treatment showed an added improvement for IKDC (International Knee Documentation Committee) scores, Lysholm scores, and Tegner scores. MRI scans performed one yr after surgical intervention showed significantly better MOCART scores for the cell-recipient group. Intraarticular injection of cultured MSCs is effective in improving both short-term clinical and MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) outcomes in patients undergoing HTO (high tibial osteotomy) and MFX (Microfracture) for varus knees with cartilage defects.
Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis.
Authors: Koh YG, Choi YJ.
Publication: Knee. 2012 Dec;19(6):902-7. doi: 10.1016/j.knee.2012.04.001. Epub 2012 May 14.
Study Method: Unblinded controlled trial
No. of patients: 50
Treatment Method: Stem cell with PRP (platelet rich plasma) injections combined with AD (arthroscopic debridement) for treating knee osteoarthritis.
Conclusion (s): Mean Lysholm, Tegner activity scale, and VAS scores of patients in the study group improved significantly by the last follow-up visit. Short-term results of our study demonstrate that infrapatellar fat pad-derived MSC therapy with intraarticular injections is safe and provides assistance in reducing pain and improving function in patients with knee osteoarthritis.
Several comparative studies (listed above) have demonstrated good evidence in the treatment of osteoarthritis. However, there are several approaches and cell lines used. More well-designed and randomised controlled trials are needed to evaluate the best approach and universal consensus. As studies continue, the methods, forms and combinations of stem cell preparations are improving, and outcomes are expected to improve as well.
Here, we have listed and compiled all recent significant scientific publications. The list was complied by running various searches on body parts and bone marrow cell types on PubMed. Each title represents a research study and is hyperlinked to the abstract in the U.S. National Library of Medicine.
Here is the list.
Cell therapy versus simultaneous contralateral decompression in symptomatic corticosteroid osteonecrosis: a thirty year follow-up prospective randomized study of one hundred and twenty five adult patients.
Authors: Hernigou P, Dubory A, Homma Y, Guissou I, Flouzat Lachaniette CH, Chevallier N, Rouard H.
Publication: Int Orthop. 2018 Jul;42(7):1639-1649. doi: 10.1007/s00264-018-3941-8. Epub 2018 May 9.
Study Method: 30 year follow up prospective randomised controlled study.
No. of patients: 125
Treatment Method: The smaller size ON (osteonecrosis) was treated with core decompression, and the contralateral hip with the larger ON was treated with percutaneous mesenchymal cell (MSC) injection obtained from bone marrow concentration.
Conclusion(s): Core decompression with bone marrow injection improved the outcome of the disease as compared with core decompression alone in the same patient.Cell therapy versus simultaneous contralateral decompression in symptomatic corticosteroid osteonecrosis: a thirty year follow-up prospective randomized study of one hundred and twenty five adult patients.
Authors: Hernigou P, Dubory A, Homma Y, Guissou I, Flouzat Lachaniette CH, Chevallier N, Rouard H.
Publication: Int Orthop. 2018 Jul;42(7):1639-1649. doi: 10.1007/s00264-018-3941-8. Epub 2018 May 9.
Study Method: 30 year follow up prospective randomised controlled study.
No. of patients: 125
Treatment Method: The smaller size ON (osteonecrosis) was treated with core decompression, and the contralateral hip with the larger ON was treated with percutaneous mesenchymal cell (MSC) injection obtained from bone marrow concentration.
A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions.
Authors: Centeno CJ, Al-Sayegh H, Freeman MD, Smith J, Murrell WD, Bubnov R.
Publication: Int Orthop. 2016 Aug;40(8):1755-1765. doi: 10.1007/s00264-016-3162-y. Epub 2016 Mar 30.
Study Method: 9 years follow up prospective study.
No. of patients: 2,372
Treatment Method: All patients underwent an MSC-based (mesenchymal stem cell based), percutaneous injection treatment of an orthopaedic condition between December 2005 and September 2014 at one of 18 clinical facilities. Treated areas of the body included the knee, hip, ankle/foot, hand/wrist, elbow, shoulder, and spine.
Conclusion (s): Lowest rate of adverse events was among those patients receiving BMC (bone marrow concentrate) injections alone, but the higher rate of AEs for BMC plus adipose and cultured cells was readily explained by the nature of the therapy or the longer follow-up. There was no clinical evidence to suggest that treatment with MSCs of any type in this study increased the risk of neoplasm (cancer).
Return to Sports After Bone Marrow-Derived Cell Transplantation for Osteochondral Lesions of the Talus (Ankle).
Authors: Vannini F, Cavallo M, Ramponi L, Castagnini F, Massimi S, Giannini S, Buda RE.
Publication: Cartilage. 2017 Jan;8(1):80-87. Epub 2016 Apr 12.
Study Method: Case series, 48 months follow up.
No. of patients: 140
Treatment Method: A "one-step" BMDCT (bone marrow derived cell transplantation) repair of OLT (osteochondral lesion of the talus. All the patients had the cells harvested from the iliac crest, condensed and loaded on a scaffold, and then implanted.
Conclusion (s): "One-step" BMDCT repair of OLT had good clinical results that was durable over time in athletes, permitting a return to sports at pre-injury level in the majority of patients. The preoperative presence of impingement and articular degeneration were the main negative prognostic factors.
Authors: Centeno CJ, Al-Sayegh H, Bashir J, Goodyear S, Freeman MD.
Publication: BMC Musculoskelet Disord. 2015 Sep 18;16:258. doi: 10.1186/s12891-015-0714-z.
Study Method: Retrospective study.
No. of patients: 373
Treatment Method: Data from an ongoing patient registry was culled to identify 373 patients that received bone marrow concentrate injections for the treatment of 424 osteoarthritic knee joints. The lower and higher cell count groups were defined using a threshold of 4 × 10(8) cells. There were 224 and 185 knee joints treated in the lower (≤4 × 10(8)) and higher (>4 × 10(8)) cell count groups respectively.
Conclusion (s): Improved function and reduced pain was observed in patients treated with a bone marrow concentrate protocol regardless of cellular dose; however, patients receiving a higher concentration of cells reported a better pain outcome in comparison with the lower dose group. These preliminary findings suggest that cell dose may be an important factor governing clinical outcomes in autologous bone marrow concentrate treatment of knee osteoarthritis. Further studies using a larger patient population may help elucidate these findings.
Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): Preclinical and clinical trial in osteoarthritis of the knee joint.
Authors: Gupta PK, Chullikana A, Rengasamy M, Shetty N, Pandey V, Agarwal V, Wagh SY, Vellotare PK, Damodaran D, Viswanathan P, Thej C, Balasubramanian S, Majumdar AS.
Publication: Arthritis Res Ther. 2016 Dec 20;18(1):301.
Study Method: Double blinded controlled trial.
No. of patients: 60
Treatment Method: The in vitro differentiation potential of adult human bone marrow derived, cultured, pooled, allogeneic MSCs (mesenchymal stem cells) injected into knee joint with different doses of cells (25, 50, 75, or 150 million cells) or placebo.
Conclusion (s): Intraarticular administration of Stempeucel was safe, and a trend towards improvement was seen in the 25-million-cell dose group in all subjective parameters Adverse events were predominant in the higher dose groups. Intraarticular administration of Stempeucel is safe. A 25-million cell dose may be the most effective among the doses tested for pain reduction.
Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft.
Authors: Centeno CJ, Pitts J, Al-Sayegh H, Freeman M.
Publication: Biomed Res Int. 2014;2014:370621. doi: 10.1155/2014/370621. Epub 2014 Sep 7.
Study Method: Retrospective study. Treatment registry data for patients who underwent BMC procedures with and without an adipose graft were analyzed.
No. of patients: 681
Treatment Method: Autologous bone marrow concentrate (BMC) with and without an adipose graft, for treatment of knee osteoarthritis (OA).
Conclusion(s): BMC (bone marrow concentrate) injections for knee OA showed encouraging outcomes and a low rate of AEs. Addition of an adipose graft to the BMC did not provide a detectible benefit over BMC alone.
Authors: Hernigou P, Homma Y, Flouzat-Lachaniette CH, Poignard A, Chevallier N, Rouard H.
Publication: J Bone Joint Surg Am. 2013 Dec 18;95(24):2215-21. doi: 10.2106/JBJS.M.00261.
Study Method: Patients were monitored for cancer incidence from the date of the first operation (1990) until death, or until December 31, 2011. The mean follow-up time was 12.5 years (range, five to twenty-two years).
No. of patients: 1873
Treatment Method: Patients who had received autologous bone marrow-derived stromal progenitor cells to treat orthopaedic lesions.
Authors: Koh YG, Kwon OR, Kim YS, Choi YJ, Tak DH.
Publication: Arthroscopy. 2016 Jan;32(1):97-109. doi: 10.1016/j.arthro.2015.09.010. Epub 2015 Nov 14.
Study Method: Unblinded prospective randomised controlled trial
No. of patients: 80
Treatment Method: Compare ADSCs (adipose derived stem cells) with fibrin glue and MFX (microfracture) versus MFX (microfracture) alone for the treatment of cartilage defects in the knee.
Conclusion (s): Significantly better signal intensity was observed for the repair tissue in ADSCs with fibrin glue and MFX. Compared with MFX alone, MFX and ADSCs with fibrin glue provided radiologic and KOOS (Knee Injury and Osteoarthritis Outcome Score) pain and symptom sub-score improvements.
Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: A randomized, double-blind, controlled study.
Authors: Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M.
Publication: J Bone Joint Surg Am. 2014 Jan 15;96(2):90-8. doi: 10.2106/JBJS.M.00058.
Study Method: Randomized, double-blind, controlled study.
No. of patients: 55
Treatment Method: Allogeneic MSCs (mesenchymal stem cells) via intraarticular injection to the knee following partial medial meniscectomy.
Conclusion (s): There was significantly increased meniscal volume determined by quantitative MRI (magnetic resonance imaging) 24% of patients in group A and 6% in group B at 12 months post-meniscectomy. Patients experienced a significant reduction in pain compared to control. There was evidence of meniscus regeneration and improvement in knee pain following treatment with allogeneic human MSCs (mesenchymal stem cells).
Authors: Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M.
Publication: J Bone Joint Surg Am. 2014 Jan 15;96(2):90-8. doi: 10.2106/JBJS.M.00058.
Study Method: Randomized, double-blind, controlled study.
No. of patients: 55
Treatment Method: Allogeneic MSCs (mesenchymal stem cells) via intraarticular injection to the knee following partial medial meniscectomy.
Conclusion (s): There was significantly increased meniscal volume determined by quantitative MRI (magnetic resonance imaging) 24% of patients in group A and 6% in group B at 12 months post-meniscectomy. Patients experienced a significant reduction in pain compared to control. There was evidence of meniscus regeneration and improvement in knee pain following treatment with allogeneic human MSCs (mesenchymal stem cells).
Intraarticular injections of HA (hyaluronic acid) with and without PBSC (peripheral blood stem cells).
Authors: Saw KY, Anz A, Siew-Yoke Jee C, Merican S, Ching-Soong Ng R, Roohi SA, Ragavanaidu K.
Publication: Arthroscopy. 2013 Apr;29(4):684-94. doi: 10.1016/j.arthro.2012.12.008. Epub 2013 Feb 4.
Study Method: Randomized, unblinded, controlled study.
No. of patients: 50
Treatment Method: Intra-articular injections of HA with and without PBSC.
Conclusion (s): The total ICRS II (International Cartilage Repair Society Visual Assessment Scale II) histologic scores for the control group averaged 957, and they averaged 1,066 for the intervention group. On evaluation of the MRI morphologic scores, the control group averaged 8.5 and the intervention group averaged 9.9. After arthroscopic subchondral drilling into grade 3 and 4 chondral lesions, postoperative intraarticular injections of autologous PBSC in combination with HA resulted in an improvement of the quality of articular cartilage repair over the same treatment without PBSC (peripheral blood stem cells).
Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: A prospective, randomized controlled clinical trial with 2 years’ follow-up.
Authors: Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH.
Publication: Arthroscopy. 2013 Dec;29(12):2020-8. doi: 10.1016/j.arthro.2013.09.074.
Study Method: Prospective unblinded controlled trial.
No. of patients: 56
Treatment Method: Intraarticular cultured autologous BM-MSCs (bone marrow mesenchymal stem cells) injections in conjunction with MFX and medial opening-wedge HTO (high tibial osteotomy).
Conclusion (s): The effect of treatment showed an added improvement for IKDC (International Knee Documentation Committee) scores, Lysholm scores, and Tegner scores. MRI scans performed one yr after surgical intervention showed significantly better MOCART scores for the cell-recipient group. Intraarticular injection of cultured MSCs is effective in improving both short-term clinical and MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) outcomes in patients undergoing HTO (high tibial osteotomy) and MFX (Microfracture) for varus knees with cartilage defects.
Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis.
Authors: Koh YG, Choi YJ.
Publication: Knee. 2012 Dec;19(6):902-7. doi: 10.1016/j.knee.2012.04.001. Epub 2012 May 14.
Study Method: Unblinded controlled trial
No. of patients: 50
Treatment Method: Stem cell with PRP (platelet rich plasma) injections combined with AD (arthroscopic debridement) for treating knee osteoarthritis.
Conclusion (s): Mean Lysholm, Tegner activity scale, and VAS scores of patients in the study group improved significantly by the last follow-up visit. Short-term results of our study demonstrate that infrapatellar fat pad-derived MSC therapy with intraarticular injections is safe and provides assistance in reducing pain and improving function in patients with knee osteoarthritis.
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