Stem Cells in Arthroscopy

Abstract

We are confident by nature.However, when it comes to biologics in arthroscopy, we still have a lot to learn. Most of the literature on biologics, tissue engineering, growth factors, and stem cells shows that there is great variability that must be accounted for. And some published related research results are promising.1Lubowitz J.H. Poehling G.G. Don't know much biology: Redux.Arthroscopy. 2008; 24: 127-129Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 2Lubowitz J.H. Poehling G.G. Arthroscopy, anatomy, and translational research.Arthroscopy. 2007; 23: 233-234Abstract Full Text Full Text PDF Scopus (11) Google Scholar, 3Lubowitz J.H. Poehling G.G. Shoulder, hip, knee, and PRP.Arthroscopy. 2010; 26: 141-142Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 4Lubowitz J.H. Poehling G.G. Saving our cells: Advances in tissue engineering for focal cartilage defects.Arthroscopy. 2009; 25: 115-116Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 5Lubowitz J.H. Poehling G.G. Tissue engineering: A call for manuscripts.Arthroscopy. 2008; 24: 623-624Abstract Full Text Full Text PDF Scopus (8) Google ScholarIn the current issue, readers will find a “must read” systematic review of the literature. We are grateful to our contributors Ahmad, Wardale, Brooks, Henson, Noorani, and Rushton, of the Orthopaedic Research Unit at Cambridge University in England for “Exploring the Application of Stem Cells in Tendon Repair and Regeneration.”6Ahmad Z. Wardale J. Brooks R. Henson F. Noorani A. Rushton N. Exploring the application of stem cells in tendon repair and regeneration.Arthroscopy. 2012; 28: 1018-1029Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar A limitation of their review is that the articles included range from Levels of evidence II to IV. The strength of the review is the clear writing, the excellent quality of the methods, and the clear, thought-provoking conclusions.In addition, your letters to the editor are heating up,7Soler F. Soler R. Peirau X. Orozco L. Rapid isolation of human stem cells.Arthroscopy. 2012; 28: 895-896PubMed Scopus (3) Google Scholar, 8Beitzel K. McCarthy M.B. Cote M.P. et al.Author's reply.Arthroscopy. 2012; 28: 896-897Scopus (3) Google Scholar, 9e Souza B.G.S. Hip arthroscopy catastrophic failure: What happened to the joint?.Arthroscopy. 2012; 28: 893-894PubMed Google Scholar, 10Mei-Dan O. McConkey M.O. Brick M. Author's reply.Arthroscopy. 2012; 28: 894-895Scopus (1) Google Scholar, 11Gàdek A. Wordliczek J. Zajaczkowska R. Evaluation of analgesic efficacy of intra-articular opioids (morphine, fentanyl) after arthroscopic knee surgery.Arthroscopy. 2012; 28: 897-898PubMed Scopus (4) Google Scholar, 12Mitra S. Author's reply.Arthroscopy. 2012; 28: 898-899Scopus (1) Google Scholar and our focus is the letter from F. Soler, R. Soler, Peirau, and Orozco of Barcelona,7Soler F. Soler R. Peirau X. Orozco L. Rapid isolation of human stem cells.Arthroscopy. 2012; 28: 895-896PubMed Scopus (3) Google Scholar expressing their concern that there may be confusion about the recent article “Rapid Isolation of Human Stem Cells (Connective Progenitor Cells) From the Distal Femur During Arthroscopic Knee Surgery” by Beitzel et al.13Beitzel K. McCarthy M.B. Cote M.P. et al.Rapid isolation of human stem cells (connective progenitor cells) from the distal femur during arthroscopic knee surgery.Arthroscopy. 2012; 28: 74-84Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Soler et al. are “… afraid that this reading matter may lead some others to misunderstand it, and it is important to clarify some concepts … .” They assert that “The healing potential of cellular therapy is based on the quality of the cellular product and on the dose … cultivation from mononucleated cells (in a laboratory, a laborious process) is considered necessary if the aim is to obtain a significant dose of progenitor cells … the application of a weak number of progenitor cells … is not efficient … So it is important to make the difference, in scientific publications as well as in the medical practice, between products that actually are self-graft and other products that belong to the ‘advanced therapies’ and that, at least in European Union, are considered as drugs … ‘drugs’ are the centrifuged bone marrow products that some apply by joint infusion with therapeutic intentions. This change in the place and function of bone marrow requires a regulated experimentation that proves its safety before its clinical application.”Your Editors are trying to understand if these regulations are similar to regulatory concerns in the United States between autologous grafting and homologous tissue engineering, or are there really clinically relevant differences?The authors wrote in reply to Soler's letter, saying, “In our opinion, … different research groups use (1) multiple methods of cell procurement and (2) different differentiation media for the determination of the final cell number. It was never the intention of our study and it is difficult to directly compare amounts of isolated cells between previously published studies, because of variable isolation methods, culture time until CFU formation and specifically the use of various differentiation media exist, resulting in diverse outcome determinations. Additionally, within the specific literature, no overall agreement on the optimal isolation method, passage time, differentiation medium, and appropriate number of MSCs exist. Therefore, scientists and surgeons can chose out of a plethora of methods with only low levels of evidence available to prove their therapeutic effect. There is a wide discussion on which additional factors are needed to improve the effects of MSC application with the aim of improvement of the healing environment in orthopaedic surgery.”8Beitzel K. McCarthy M.B. Cote M.P. et al.Author's reply.Arthroscopy. 2012; 28: 896-897Scopus (3) Google ScholarThese discussions are important because, in addition to the methods cited above, Mazzocca et al. have previously extracted stem cells from the humerus during rotator cuff repair, in order to produce connective tissue progenitor cells and, in addition, found that bone marrow–derived stem cells differentiate into tendon-like cells when tagged with insulin.14Mazzocca A.D. McCarthy M.B.R. Chowaniec D.M. Cote M.P. Arciero R.A. Drissi H. Rapid isolation of human stem cells (connective tissue progenitor cells from the proximal humerus during arthroscopic rotator cuff surgery.Am J Sports Med. 2010; 38: 1438-1447Crossref PubMed Scopus (120) Google Scholar, 15Mazzocca A.D. McCarthy M.B.R. Chowaniec D. et al.Bone marrow–derived mesenchymal stem cells obtained during arthroscopic rotator cuff repair surgery show potential for tendon cell differentiation after treatment with insulin.Arthroscopy. 2011; 27: 1459-1471Abstract Full Text Full Text PDF PubMed Scopus (90) Google ScholarWe are fascinated by the possibility that, some day, cells extracted from the humeral head could be used to enhance arthroscopic shoulder rotator cuff repair, and cells extracted from the distal femur13Beitzel K. McCarthy M.B. Cote M.P. et al.Rapid isolation of human stem cells (connective progenitor cells) from the distal femur during arthroscopic knee surgery.Arthroscopy. 2012; 28: 74-84Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar could be used to enhance arthroscopic knee anterior cruciate ligament reconstruction.16Lim J.-K. Hui J. Li L. Thambyah A. Goh J. Lee E.-H. Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction.Arthroscopy. 2004; 20: 899-910Abstract Full Text Full Text PDF PubMed Scopus (227) Google ScholarThe possibilities are endless.And let's not forget that McIlwraith, Frisbie, Rodkey, Kisiday, Werpy, Kawcak, and Steadman17McIlwraith C.W. Frisbie D.D. Rodkey W.G. et al.Evaluation of intra-articular mesenchymal stem cells to augment healing of microfractured chondral defects.Arthroscopy. 2011; 27: 1552-1561Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar evaluated intra-articular injection of bone marrow–derived mesenchymal stem cells to augment healing of microfractured chondral defects compared with microfracture alone in horses.Although there were no significant clinical or histologic differences between groups, there was some suggestion that bone marrow–derived mesenchymal stem cells did enhance cartilage repair quality.In addition, Saw, Anz, Merican, Tay, Ragavanaidu, Jee, and McGuire reported “Articular Cartilage Regeneration With Autologous Peripheral Blood Progenitor Cells and Hyaluronic Acid After Arthroscopic Subchondral Drilling: A Report of 5 Cases With Histology.”18Saw K.-Y. Anz A. Merican S. et al.Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: A report of 5 cases with histology.Arthroscopy. 2011; 27: 493-506Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Patients with knee cartilage lesions had arthroscopic subchondral drilling followed by postoperative intra-articular injection of peripheral blood progenitor (stem) cells. Second-look arthroscopic biopsy and histologic examination revealed articular hyaline cartilage regeneration, and postoperative radiographs even suggested joint space restoration.As we have previously opined, “To be honest, the idea that articular hyaline cartilage regeneration and joint space restoration could be possible as a result of a single-stage arthroscopic procedure followed by injections seems too good to be true … At the end of the day … we believe many will agree that stem cells have vast potential. In the future, we are prepared for inevitable steps backward, but today we are optimists who advance two steps forward.”19Lubowitz J.H. Provencher M.T. Poehling G.G. Two steps forward, one step back.Arthroscopy. 2011; 27: 1453-1455Abstract Full Text Full Text PDF PubMed Scopus (16) Google ScholarTo borrow a Lincolnesque construction: We are confident of nature, by nature, and for nature.Some published research results are promising relevant to stem cells, and the vast magnitude of biologic variability is the obstacle researchers currently address. We are confident by nature. However, when it comes to biologics in arthroscopy, we still have a lot to learn. Most of the literature on biologics, tissue engineering, growth factors, and stem cells shows that there is great variability that must be accounted for. And some published related research results are promising.1Lubowitz J.H. Poehling G.G. Don't know much biology: Redux.Arthroscopy. 2008; 24: 127-129Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 2Lubowitz J.H. Poehling G.G. Arthroscopy, anatomy, and translational research.Arthroscopy. 2007; 23: 233-234Abstract Full Text Full Text PDF Scopus (11) Google Scholar, 3Lubowitz J.H. Poehling G.G. Shoulder, hip, knee, and PRP.Arthroscopy. 2010; 26: 141-142Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 4Lubowitz J.H. Poehling G.G. Saving our cells: Advances in tissue engineering for focal cartilage defects.Arthroscopy. 2009; 25: 115-116Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 5Lubowitz J.H. Poehling G.G. Tissue engineering: A call for manuscripts.Arthroscopy. 2008; 24: 623-624Abstract Full Text Full Text PDF Scopus (8) Google Scholar In the current issue, readers will find a “must read” systematic review of the literature. We are grateful to our contributors Ahmad, Wardale, Brooks, Henson, Noorani, and Rushton, of the Orthopaedic Research Unit at Cambridge University in England for “Exploring the Application of Stem Cells in Tendon Repair and Regeneration.”6Ahmad Z. Wardale J. Brooks R. Henson F. Noorani A. Rushton N. Exploring the application of stem cells in tendon repair and regeneration.Arthroscopy. 2012; 28: 1018-1029Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar A limitation of their review is that the articles included range from Levels of evidence II to IV. The strength of the review is the clear writing, the excellent quality of the methods, and the clear, thought-provoking conclusions. In addition, your letters to the editor are heating up,7Soler F. Soler R. Peirau X. Orozco L. Rapid isolation of human stem cells.Arthroscopy. 2012; 28: 895-896PubMed Scopus (3) Google Scholar, 8Beitzel K. McCarthy M.B. Cote M.P. et al.Author's reply.Arthroscopy. 2012; 28: 896-897Scopus (3) Google Scholar, 9e Souza B.G.S. Hip arthroscopy catastrophic failure: What happened to the joint?.Arthroscopy. 2012; 28: 893-894PubMed Google Scholar, 10Mei-Dan O. McConkey M.O. Brick M. Author's reply.Arthroscopy. 2012; 28: 894-895Scopus (1) Google Scholar, 11Gàdek A. Wordliczek J. Zajaczkowska R. Evaluation of analgesic efficacy of intra-articular opioids (morphine, fentanyl) after arthroscopic knee surgery.Arthroscopy. 2012; 28: 897-898PubMed Scopus (4) Google Scholar, 12Mitra S. Author's reply.Arthroscopy. 2012; 28: 898-899Scopus (1) Google Scholar and our focus is the letter from F. Soler, R. Soler, Peirau, and Orozco of Barcelona,7Soler F. Soler R. Peirau X. Orozco L. Rapid isolation of human stem cells.Arthroscopy. 2012; 28: 895-896PubMed Scopus (3) Google Scholar expressing their concern that there may be confusion about the recent article “Rapid Isolation of Human Stem Cells (Connective Progenitor Cells) From the Distal Femur During Arthroscopic Knee Surgery” by Beitzel et al.13Beitzel K. McCarthy M.B. Cote M.P. et al.Rapid isolation of human stem cells (connective progenitor cells) from the distal femur during arthroscopic knee surgery.Arthroscopy. 2012; 28: 74-84Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Soler et al. are “… afraid that this reading matter may lead some others to misunderstand it, and it is important to clarify some concepts … .” They assert that “The healing potential of cellular therapy is based on the quality of the cellular product and on the dose … cultivation from mononucleated cells (in a laboratory, a laborious process) is considered necessary if the aim is to obtain a significant dose of progenitor cells … the application of a weak number of progenitor cells … is not efficient … So it is important to make the difference, in scientific publications as well as in the medical practice, between products that actually are self-graft and other products that belong to the ‘advanced therapies’ and that, at least in European Union, are considered as drugs … ‘drugs’ are the centrifuged bone marrow products that some apply by joint infusion with therapeutic intentions. This change in the place and function of bone marrow requires a regulated experimentation that proves its safety before its clinical application.” Your Editors are trying to understand if these regulations are similar to regulatory concerns in the United States between autologous grafting and homologous tissue engineering, or are there really clinically relevant differences? The authors wrote in reply to Soler's letter, saying, “In our opinion, … different research groups use (1) multiple methods of cell procurement and (2) different differentiation media for the determination of the final cell number. It was never the intention of our study and it is difficult to directly compare amounts of isolated cells between previously published studies, because of variable isolation methods, culture time until CFU formation and specifically the use of various differentiation media exist, resulting in diverse outcome determinations. Additionally, within the specific literature, no overall agreement on the optimal isolation method, passage time, differentiation medium, and appropriate number of MSCs exist. Therefore, scientists and surgeons can chose out of a plethora of methods with only low levels of evidence available to prove their therapeutic effect. There is a wide discussion on which additional factors are needed to improve the effects of MSC application with the aim of improvement of the healing environment in orthopaedic surgery.”8Beitzel K. McCarthy M.B. Cote M.P. et al.Author's reply.Arthroscopy. 2012; 28: 896-897Scopus (3) Google Scholar These discussions are important because, in addition to the methods cited above, Mazzocca et al. have previously extracted stem cells from the humerus during rotator cuff repair, in order to produce connective tissue progenitor cells and, in addition, found that bone marrow–derived stem cells differentiate into tendon-like cells when tagged with insulin.14Mazzocca A.D. McCarthy M.B.R. Chowaniec D.M. Cote M.P. Arciero R.A. Drissi H. Rapid isolation of human stem cells (connective tissue progenitor cells from the proximal humerus during arthroscopic rotator cuff surgery.Am J Sports Med. 2010; 38: 1438-1447Crossref PubMed Scopus (120) Google Scholar, 15Mazzocca A.D. McCarthy M.B.R. Chowaniec D. et al.Bone marrow–derived mesenchymal stem cells obtained during arthroscopic rotator cuff repair surgery show potential for tendon cell differentiation after treatment with insulin.Arthroscopy. 2011; 27: 1459-1471Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar We are fascinated by the possibility that, some day, cells extracted from the humeral head could be used to enhance arthroscopic shoulder rotator cuff repair, and cells extracted from the distal femur13Beitzel K. McCarthy M.B. Cote M.P. et al.Rapid isolation of human stem cells (connective progenitor cells) from the distal femur during arthroscopic knee surgery.Arthroscopy. 2012; 28: 74-84Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar could be used to enhance arthroscopic knee anterior cruciate ligament reconstruction.16Lim J.-K. Hui J. Li L. Thambyah A. Goh J. Lee E.-H. Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction.Arthroscopy. 2004; 20: 899-910Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar The possibilities are endless. And let's not forget that McIlwraith, Frisbie, Rodkey, Kisiday, Werpy, Kawcak, and Steadman17McIlwraith C.W. Frisbie D.D. Rodkey W.G. et al.Evaluation of intra-articular mesenchymal stem cells to augment healing of microfractured chondral defects.Arthroscopy. 2011; 27: 1552-1561Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar evaluated intra-articular injection of bone marrow–derived mesenchymal stem cells to augment healing of microfractured chondral defects compared with microfracture alone in horses. Although there were no significant clinical or histologic differences between groups, there was some suggestion that bone marrow–derived mesenchymal stem cells did enhance cartilage repair quality. In addition, Saw, Anz, Merican, Tay, Ragavanaidu, Jee, and McGuire reported “Articular Cartilage Regeneration With Autologous Peripheral Blood Progenitor Cells and Hyaluronic Acid After Arthroscopic Subchondral Drilling: A Report of 5 Cases With Histology.”18Saw K.-Y. Anz A. Merican S. et al.Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: A report of 5 cases with histology.Arthroscopy. 2011; 27: 493-506Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Patients with knee cartilage lesions had arthroscopic subchondral drilling followed by postoperative intra-articular injection of peripheral blood progenitor (stem) cells. Second-look arthroscopic biopsy and histologic examination revealed articular hyaline cartilage regeneration, and postoperative radiographs even suggested joint space restoration. As we have previously opined, “To be honest, the idea that articular hyaline cartilage regeneration and joint space restoration could be possible as a result of a single-stage arthroscopic procedure followed by injections seems too good to be true … At the end of the day … we believe many will agree that stem cells have vast potential. In the future, we are prepared for inevitable steps backward, but today we are optimists who advance two steps forward.”19Lubowitz J.H. Provencher M.T. Poehling G.G. Two steps forward, one step back.Arthroscopy. 2011; 27: 1453-1455Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar To borrow a Lincolnesque construction: We are confident of nature, by nature, and for nature. Some published research results are promising relevant to stem cells, and the vast magnitude of biologic variability is the obstacle researchers currently address.