Tag Archive | stem cell
January 14, 2020  

Curb Your Enthusiasm about Stem Cells for Knee OA

Mark Miller, MD is a professor of orthopaedic surgery at the University of Virginia, founder and co-director of the Miller Review Courses, and former deputy editor for sports medicine at JBJS. In a piece he authored recently for The Conversation, Dr. Miller labeled stem-cell treatments for knee osteoarthritis (OA) “unproven, expensive, and potentially dangerous.”

About 2 years ago, Dr. Miller himself underwent bilateral knee replacements for severe knee arthritis. He understands why patients may fall prey to misleading marketing hype that claims stem cell treatments can help people postpone or entirely avoid knee replacement. (See related OrthoBuzz post.) “My mission,” he writes, is to “try to keep the enthusiasm regarding new cutting-edge options in check,” adding that “the excitement about stem cells has outpaced the science,” especially when it comes to knee OA.

Although stem cell injections have been promoted as a way to regenerate cartilage in arthritic joints, Dr. Miller echoes the American Association of Hip and Knee Surgeons when he says that “there are no proven…therapies that can delay or reverse the progressive joint destruction that occurs with osteoarthritis.” Moreover, the do-no-harm part of the Hippocratic oath requires doctors to give their patients “a clear picture of the potential benefits and side effects of their treatment options,” writes Dr. Miller, who cited a December 20, 2018 New York Times article describing 12 patients who were hospitalized for serious infections after receiving stem cell injections into their knees, shoulders, or spines.

For their part, Dr. Miller says patients should employ the “buyer beware” concept because stem cell therapy for osteoarthritis is not only unproven but also expensive—and usually not covered by medical insurance. The best approach to knee OA, says Dr. Miller, is what is nowadays called shared decision making: “Physicians need to work closely with patients to help them understand their options and which choice may be best for them.”

November 21, 2019  

What’s New in Orthopaedic Rehabilitation 2019

Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all such OrthoBuzz summaries.

This month, co-author Nitin B. Jain, MD, MSPH selected the most clinically compelling findings from the 40 studies summarized in the November 20, 2019 “What’s New in Orthopaedic Rehabilitation.”

Pain Management
–A randomized controlled trial compared pain-related function, pain intensity, and adverse effects among 240 patients with chronic back, hip, or knee pain who were randomized to receive opioids or non-opioid medication.1 After 12 months, there were no between-group differences in pain-related function. Statistically, the pain intensity score was significantly lower in the non-opioid group, although the difference is probably not clinically meaningful. Adverse events were significantly more frequent in the opioid group.

–A series of nested case-control studies found that the use of the NSAID diclofenac was associated with an increase in the risk of myocardial infarction in patients with spondyloarthritis and osteoarthritis, relative to those taking the NSAID naproxen.2

–Intra-articular injections of corticosteroids or hyaluronic acid are often used for pain relief prior to an eventual total knee arthroplasty (TKA). An analysis of insurance data found that patients who had either type of injection within three months of a TKA had a higher risk of periprosthetic joint infection (PJI) after the operation than those who had injections >3 months prior to TKA.

Partial-Thickness Rotator Cuff Tears
–A randomized controlled trial of 78 patients with a partial-thickness rotator cuff compared outcomes of those who underwent immediate arthroscopic repair with outcomes among those who delayed operative repair until completing 6 months of nonoperative treatment, which included activity modification, PT, corticosteroid injections, and NSAIDs.3 At 2 and 12 months post-repair, both groups demonstrated improved function relative to initial evaluations. At the final follow-up, there were no significant between-group differences in range of motion, VAS, Constant score, or ASES score. Ten (29.4%) of the patients in the delayed group dropped out of the study due to symptom improvement.

Stem Cell Therapy
–A systematic review that assessed 46 studies investigating stem cell therapy for articular cartilage repair4 found low mean methodology scores, indicating overall poor-quality research. Only 1 of the 46 studies was classified as excellent, prompting the authors to conclude that evidence to support the use of stem cell therapy for cartilage repair is limited by a lack of high-quality studies and heterogeneity in the cell lines studied.

References

  1. Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, Kroenke K, Bair MJ, Noorbaloochi S. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA. 2018 Mar 6;319(9):872-82.
  2. Dubreuil M, Louie-Gao Q, Peloquin CE, Choi HK, Zhang Y, Neogi T. Risk ofcmyocardial infarction with use of selected non-steroidal anti-inflammatory drugs incpatients with spondyloarthritis and osteoarthritis. Ann Rheum Dis. 2018 Aug;77(8): 1137-42. Epub 2018 Apr 19.
  3. Kim YS, Lee HJ, Kim JH, Noh DY. When should we repair partial-thickness rotator cuff tears? Outcome comparison between immediate surgical repair versus delayed repair after 6-month period of nonsurgical treatment. Am J Sports Med. 2018 Apr;46(5):1091-6. Epub 2018 Mar 5.
  4. Park YB, Ha CW, Rhim JH, Lee HJ. Stem cell therapy for articular cartilage repair: review of the entity of cell populations used and the result of the clinical application of each entity. Am J Sports Med. 2018 Aug;46(10):2540-52. Epub 2017 Oct 12.
November 6, 2019  

Negative Findings from Level-I Trial Still a Step Forward

Donor-site morbidity from harvesting autologous bone graft has driven the decades-long search for a substitute that performs at least as well as a patient’s own bone. Much of the clinical research on donor-site morbidity is flawed by detection bias, but other factors such as operating-room time and expense are still driving the search for the ideal substitute for autologous bone. Still, the discovery of an ideal bone-graft substitute continues to be elusive.

In The November 6, 2019 issue of The Journal, Myerson et al. report findings from a Level-I trial that investigated the use of adipose-derived cellular bone matrix (ACBM) as a graft substitute in patients undergoing subtalar arthrodesis. Among 57 patients who received autograft and 52 who received ACBM, the substitute delivered lower fusion rates as determined by both CT and plain radiographic/clinical evaluations at 6 months. In addition, patients treated with autologous bone graft had lower rates of serious adverse events.

I commend the authors and funders (AlloSource) of this well-designed clinical trial for reporting these negative results, because it is often just as important to know what doesn’t work as what does. (This manuscript was submitted even after AlloSource decided to halt further production of its ACBM product in 2017.) Such transparent reporting saves other investigators and graft substitute-focused companies from going down similar avenues of investigation. Perhaps even more importantly, publishing negative results such as this might save patients from undergoing procedures with similar formulations that would probably have minimal chance of helping and could do harm.

By contributing to the scientific “process of elimination,” this study brings us one step closer to the identification of a worthy substitute for autologous bone graft.

Marc Swiontkowski, MD
JBJS Editor-in-Chief

June 25, 2019  

Stemming the Tide of Stem Cell Hype

Stem Cells for OBuzzThis post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

Despite the absence of research-based guidance, the use of stem cell therapies in musculoskeletal medicine has gained popularity and stimulated patient interest. Consequently, an international consensus was  recently established to develop strategies to improve standardization and transparency when describing cell therapies, and to develop a consensus on the contents of a standardized tool for describing cell therapies.1 The tool, dubbed DOSES, was an outgrowth of a call for improvement in communicating about cell-based therapies made during the American Academy of Orthopaedic Surgeons/National Institutes of Health Optimizing Clinical Use of Biologics Symposium in 2018.

The international experts used an iterative Delphi methodology to develop DOSES. The five components of the DOSES tool are Donor (i.e., autologous, allogeneic, xenogeneic), Origin of tissue (fat, bone marrow, etc.), Separation from other cell types/preparation method, Exhibited cell characteristics, and the Site of delivery. The tool should help clinicians, researchers, regulators, and industry professionals describe and communicate about any given stem cell treatment clearly and transparently.

In a commentary on the DOSES article, Scott Rodeo, MD notes that efforts are under way to clarify and classify stem cells by genomics, proteomics, metabolomics, and other approaches.2 Dr. Rodeo believes that the most important component of DOSES is the “E” category, information that will ultimately characterize the biologic activity of the cell preparation. He concludes by encouraging “clinicians, industry, and authors of both laboratory and clinical studies to begin the use of the DOSES tool, and possibly other algorithms, when communicating the results of cell therapy investigations.” This admonition carries over to journal editors, who, Dr. Rodeo says, should “consider adopting such reporting standards as mandatory for publication” of stem cell studies.

For stem cell therapy to progress clinically in the future, researchers and clinicians must apply a consistent nomenclature to describe cell therapies and actual cell formulations.3 This is lacking in today’s applications.

References

  1. 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 May 15;101(10):904-911. doi: 10.2106/JBJS.18.00915. PMID: 31094982
  2. Rodeo SA. A Call for Standardization in Cell Therapy Studies: Commentary on an article by Iain R. Murray, BMedSci(Hons), MRCS, MFSEM, PhD, et al.: “International Expert Consensus on a Cell Therapy Communication Tool: DOSES”. J Bone Joint Surg Am. 2019 May 15;101(10):e47. doi: 10.2106/JBJS.19.00189. PMID: 31094994.
  3. Jones IA, Chen X, Evseenko D, Vangsness CT Jr. Nomenclature Inconsistency and Selective Outcome Reporting Hinder Understanding of Stem Cell Therapy for the Knee. J Bone Joint Surg Am. 2019 Jan 16;101(2):186-195. doi: 10.2106/JBJS.17.01474. PMID: 30653050
May 28, 2019  

Meniscal Extrusions: Imaging and Repair

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

Loss of hoop stress by either medial or lateral menisci can cause meniscal extrusion, which results in increased forces on articular cartilage. The degree of meniscal extrusion is typically measured as a 2-dimensional distance with MRI. However, investigators recently used 3-D MRI to analyze the relationship between medial meniscal extrusion (MME) and femoral cartilage change in patients with these tears.1

Fifteen males (mean age of 56 years) with a medial meniscal degenerative tear (grade 3 by the Mink classification) based on MRI were included. The cartilage area was reconstructed in 3-D, and the femoral cartilage was projected in 2-D by 3-D MRI analysis. The femoral cartilage of the femorotibial joint was divided into 4 segments, and the cartilage area ratio was defined as the ratio of cartilage with thickness ≥1.0 mm in each segment. The tibial MME area (mm2) and volume (cm3), excluding osteophytes, were measured by 3-D MRI.

The projected cartilage area ratio (cartilage thickness ≥1.0 mm) at the posteromedial segment was lower than the ratio at the other 3 segments. The cartilage area ratio at the posteromedial segment was not correlated with the MME distance measured by the 2-D MRI, but it was negatively correlated with MME area (r=-0.53, p=0.045) and MME volume (r=-0.62, p=0.016) as measured by 3-D MRI. Overall, the 3-D imaging more accurately reflected cartilage damage.

Both radial tears and posterior horn degeneration can lead to meniscal extrusion. When this injury is seen acutely in younger persons, repairs are often attempted. Recently efforts have been made to do repairs in older individuals. The use of cell-seeded nanofibrous scaffolds to repair radial tears and resulting hoop-structure injuries has been studied for prevention of articular cartilage degeneration using a rabbit model.2

Synovial mesenchymal stem cells were isolated and expanded into sheets that were then wrapped onto poly(e-caprolactone) scaffolds to create stable cell/scaffold tissue-engineered constructs (TECs). Scaffold-alone or TEC + scaffold constructs were then sutured into created radial meniscal defects (12 rabbits in each group).

The TEC-scaffold group maintained the structure of the hyaline cartilage with matrix staining with Safranin O up to 12 weeks after surgery. Although the cartilage coverage decreased in both groups, the TEC-scaffold group did not become significantly worse over time, suggesting stabilization of hoop structure integrity. Only the TEC-scaffold group showed repair tissue that exhibited positive Safranin O staining in the inner zone of the meniscus.

Future studies will be required to determine the role of tissue engineering in the preservation of meniscal coverage in the face of radial tears.

References

  1. Suzuki S, Ozeki N, Kohno Y, Mizuno M, Otabe K, Katano H, Tsuji K, Suzuki K, Itai Y, Masumoto J, Koga H, Sekiya I. Medial meniscus extrusion (MME) area and MME volume determined by 3D-MRI are more sensitive than MME distance determined by 2D-MRI for evaluating cartilage loss in knees with medial meniscus degenerative tears. ORS 2019 Annual Meeting Poster No. 0514.
  2. Shimomura K, Rothrauff BB, Hart DA, Hamamoto S,  Kobayashi M,  Yoshikawa H, Tuan RS, Nakamura N. Enhanced Repair of Meniscal Hoop Structure Injuries Using An Aligned Electrospun Nanofibrous Scaffold Combined with a Mesenchymal Stem Cell-derived Tissue Engineered Construct. ORS 2019 Annual Meeting Poster No. 0519.
May 21, 2019  

NYT Cites Hype of Stem-Cell Treatments for Joint Problems

An active, 71-year old man who declined joint replacement in favor of stem-cell treatment is quoted in a recent New York Times article as saying, “They’re really quick to try to give you fake joints and make a bunch of money off you.” But the NYT article goes on to suggest that making money may be the main objective of some of the many hundreds of clinics that have sprung up around the US to offer cell-based injections to people with aging or damaged joints who want relief without surgery.

The article points out that the FDA has “taken an industry-friendly approach toward companies using unproven cell cocktails” and that the scant scientific evidence about these treatments, which include injections of platelet-rich plasma, is inconclusive.

For OrthoBuzz readers who want to dive more deeply into the scientific underpinnings (or lack thereof) related to cell therapies for joint problems, please peruse the following JBJS and JBJS Reviews articles, which have been made openly available for a limited period of time:

The main message running through all these articles is this: Effective clinical assessment and safe, optimized use of cell-based therapies demands greater attention to study methods; standards for cell harvesting, processing, and delivery; and standardized reporting of clinical and structural outcomes.

April 13, 2018  

Overselling Stem Cells?

Stem Cells for OBuzzThis post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

In orthopaedics, the term “biologics” is often applied to cell-based therapies. There are a number of centers using mesenchymal stem cells (MSCs) in musculoskeletal medicine, and a recent systematic review assessed the quality of literature and procedural specifics surrounding MSC therapy for osteoarthritis (OA)1.

The authors searched four large scientific databases for studies investigating MSCs for OA treatment. Among the 61 articles analyzed, 2,390 OA patients were treated, most with adipose-derived stem cells (ADSCs) (n = 29 studies) or bone marrow-derived stem cells (BMSCs) (n = 30 studies), though the preparation techniques varied within each group. In a subanalysis of 5 Level I and 9 Level II studies (288 patients), researchers found that 8 studies used BMSCs, 5 used ADSCs, and 1 used peripheral blood stem cells. A risk-of-bias analysis showed 5 Level I studies at low risk, 7 Level II studies at moderate risk, and 2 Level II studies at high risk. The authors concluded that although there is a “notion” that MSC therapy has a positive effect on OA patients, there is limited high-quality evidence and a dearth of long-term follow-up.

Despite the low-quality evidence and the many questions surrounding MSCs for treating OA, there are an estimated 570 clinics in the US marketing “stem cell” treatments for orthopaedic problems2. The American Academy of Orthopaedic Surgeons (AAOS) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases recently convened a symposium on this issue. According to Constance Chu, MD, professor of orthopaedic surgery at Stanford University and the symposium program chair, the objective was to establish a clear, collective impact agenda for the clinical evaluation, use, and optimization of biologics in orthopaedics, and to develop a guidance document on clinically meaningful endpoints and outcome metrics for the evaluation of biologics used in orthopaedics.

Symposium attendees examined the possible use of registries to generate clinical evidence on the use of biologics in orthopaedics. Registry models that could be employed to obtain data on practice patterns and early warning of potential issues include the American Joint Replacement Registry, the Kaiser Registry, and the International Cartilage Repair Registry. Another model could be a biorepository-linked registry similar to what has been established at the VA Hospital in Palo Alto, California, where samples from platelet-rich plasma are stored for later comparison with clinical outcomes.

References

  1. Jevotovsky DS, Alfonso AR, Einhorn TA, Chiu ES. Osteoarthritis and Stem Cell Therapy in Humans: A Systematic Review, Osteoarthritis and Cartilage (2018), doi: 10.1016/ j.joca.2018.02.906.
  2. Symposium by The American Academy of Orthopaedic Surgeons and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. “Optimizing Clinical Use of Biologics in Orthopaedic Surgery,” Feb. 15–17, 2018, at Stanford University.
December 19, 2017  

What’s New in Musculoskeletal Basic Science 2017

Specialty Update Image for OBuzz

Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.

This month, Matthew J. Allen, VetMB, PhD, author of the December 6, 2017 Specialty Update on Musculoskeletal Basic Science, summarized the five most compelling findings from among the more than 60 noteworthy studies summarized in the article.

Cartilage Repair

–Deriving induced pluripotent stem cells (iPSCs) from peripheral blood cells1 rather than from dermal fibroblasts obviates the need for in vitro expansion. This method may also serve to boost interest in the use of commercial cell-based therapies with defined potency that are available off-the-shelf and don’t require separate cell-harvesting procedures.

–The FDA recommends that large-animal models be used to corroborate basic-science findings from small-animal models. Recent work has demonstrated the efficacy of insulin-like growth factor (IGF)-1 in supporting mechanically competent repair tissue following chondrocyte implantation in a pig model.2

Infection

–Infection, especially from organisms that have developed antimicrobial resistance and/or that produce biofilms, continues to pose a challenging problem for orthopaedic surgeons. To provide a more rational and stratified approach to managing these complex cases, Getzlaf et al. recommend the use of a multidisciplinary approach in which patient-specific information about individual microorganisms is combined with detailed understandings of the vulnerabilities of candidate bacterial species.3

Aseptic Loosening

–There is a resurgence of interest in the role of subclinical infection in the etiopathogenesis of aseptic loosening. At the same time, molecular diagnostic methods for microbial infection are moving forward.4 Such methods may serve to highlight the relevance of subclinical microbial contamination as a cause of aseptic loosening.

Cartilage Imaging

–While the goal of cartilage imaging is to develop tools that are fast, inexpensive, sensitive, accurate, and noninvasive, there is growing interest in the use of more direct, invasive techniques such as optical coherence tomography (OCT),5 which could be used in vivo at the time of surgery to analyze cartilage damage.

References

  1. Li Y, Liu T, Van Halm-Lutterodt N, Chen J, Su Q, Hai Y. Reprogramming of blood cells into induced pluripotent stem cells as a new cell source for cartilage repair. Stem Cell Res Ther.2016 Feb 17;7:31.
  2. Meppelink AM, Zhao X, Griffin DJ, Erali R, Gill TJ, Bonassar LJ, Redmond RW,Randolph MA. Hyaline articular matrix formed by dynamic self-regenerating cartilage and hydrogels. Tissue Eng Part A.2016 Jul;22(13-14):962-70. Epub 2016 Jul 7.
  3. Getzlaf MA, Lewallen EA, Kremers HM, Jones DL, Bonin CA, Dudakovic A,Thaler R, Cohen RC, Lewallen DG, van Wijnen AJ. Multi-disciplinary antimicrobial strategies for improving orthopaedic implants to prevent prosthetic joint infections in hip and knee. J Orthop Res.2016 Feb;34(2):177-86. Epub 2015 Dec 29.
  4. Palmer MP, Melton-Kreft R, Nistico L, Hiller NL, Kim LH, Altman GT, Altman DT, Sotereanos NG, Hu FZ, De Meo PJ, Ehrlich GD. Polymerase chain reaction-electrospray-time-of-flight mass spectrometry versus culture for bacterial detection in septic arthritis and osteoarthritis. Genet Test Mol Biomarkers.2016 Dec;20(12):721-31. Epub 2016 Oct 17.
  5. Novakofski KD, Pownder SL, Koff MF, Williams RM, Potter HG, Fortier LA. High-resolution methods for diagnosing cartilage damage in vivo. 2016 Jan;7(1):39-51.
December 2, 2016  

Updated Knee Content from JBJS

knee-spotlight-image.pngThe recently launched JBJS Knee Spotlight offers highly relevant and potentially practice-changing knee content from the most trusted source of orthopaedic information.

Here are the five JBJS articles to which you will have full-text access through the Knee Spotlight during the month of December 2016:

  • Adult Human Mesenchymal Stem Cells Delivered via Intra-Articular Injection to the Knee Following Partial Medial Meniscectomy

  • Computer Navigation for Total Knee Arthroplasty Reduces Revision Rate for Patients Less Than Sixty-five Years of Age

  • Comparison of Closing-Wedge and Opening-Wedge High Tibial Osteotomy for Medial Compartment Osteoarthritis of the Knee

  • Weight-Bearing Compared with Non-Weight-Bearing Following Osteochondral Autograft Transfer for Small Defects in Weight-Bearing Areas in the Femoral Articular Cartilage of the Knee

  • Early Patient Outcomes After Primary Total Knee Arthroplasty with Quadriceps-Sparing Subvastus and Medial Parapatellar Techniques

Knee studies offered on the JBJS Knee Spotlight will be updated monthly, so check the site often.

Visit the JBJS Knee Spotlight website today.