ICRS 2019 - Conference Calendar
14.0.1 - What is the Real Science?
Mesenchymal stem cells (MSCs) have long been proposed as a potential cell source for musculoskeletal regeneration. Within the cartilage field there have been several efforts to develop novel therapeutic strategies using these cells (Johnstone et al., 2013). Broadly speaking MSC therapies can be split into two categories; those that use freshly isolated cells, and those that use monolayer expanded cells. This distinction brings significant ramifications, both in terms of regulatory requirements and in the mechanism of action. From a scientific perspective, there have been two main challenges that have delayed the translation of MSCs into the clinic. Insufficient tools to adequately characterize the cell populations obtained and a lack of a detailed understanding of the mechanism of action of the implanted cells.
Naïve cells are already commonly utilized in the clinic in the form of marrow stimulation techniques or intra-operative cell transfer of bone marrow aspirate concentrates (BMAC). The ease of application has been a major driver although it is widely accepted that the repair tissue produced often has inferior properties due to its fibrocartilage nature (Farr et al., 2011). This in itself is not an impediment to their use, as delaying the need for a prosthetic joint is still a great advantage as years of fitness and life expectancy increase.
Monolayer expansion of adherent MSCs is an attractive alternative strategy due to the increase in numbers than can then be implanted. This process is fraught with difficulties as it is known the expansion process can lead to major changes in cellular function (Bara et al., 2014). Whether this is due to changes in cell behavior during expansion (phenotypic drift), or whether it is due to the expansion conditions preferentially selecting for a subpopulation is unclear with data suggesting both may be possible. Multicolor barcode lentivirus labelling has shown that a smaller number of clones become dominant during expansion (Selich et al., 2016). While adapting monolayer expansion conditions during the last few days of culture can also prime cells to be more receptive to differentiation. This particular issue has been highlighted in an article by Arnold Caplan that postulates monolayer expanded cells do not behave as naïve MSCs and raises the question as to whether tripotency, a commonly used MSC assessment, is actually an in vitro artifact (Caplan, 2017).
The use of accurate markers to identify the cells being studied is the central issue around most other topics revolve. With no marker being truly MSC specific, consensus and reproducibility is almost impossible to achieve. This compounds the problem that phenotype and function of monolayer expanded cells will vary depending on several factors, such as serum batch, making comparisons between laboratories difficult. Furthermore, markers predictive of MSC function are lacking. Commonly used CD markers do not provide an indication of function which limits their use (Sacchetti et al., 2016). Work in this area is increasing from our laboratory and others (Dickinson et al., 2017; Loebel et al., 2015) and this will hopefully lead to new assays being developed that can predict potency of individual donors.
The use of monolayer expanded cells is hindered by a number of still open questions. Are undifferentiated or predifferentiated cells preferable in a clinical setting? Does monolayer expansion under 21% oxygen select for a population of cells that are more susceptible to cell death when placed in the hypoxic injured joint? Is the main mechanism of action cell differentiation or paracrine activity? The answers to these questions are likely to be interrelated and more work needs to be done.
Bara JJ, Richards RG, Alini M, Stoddart MJ (2014) Concise review: Bone marrow-derived mesenchymal stem cells change phenotype following in vitro culture: implications for basic research and the clinic. Stem Cells 32: 1713-1723.
Caplan AI (2017) Mesenchymal Stem Cells: Time to Change the Name! Stem Cells Transl Med 6: 1445-1451.
Dickinson SC, Sutton CA, Brady K, Salerno A, Katopodi T, Williams RL, West CC, Evseenko D, Wu L, Pang S, Ferro de Godoy R, Goodship AE, Peault B, Blom AW, Kafienah W, Hollander AP (2017) The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation. Stem Cells.
Farr J, Cole B, Dhawan A, Kercher J, Sherman S (2011) Clinical cartilage restoration: evolution and overview. ClinOrthopRelat Res 469: 2696-2705.
Johnstone B, Alini M, Cucchiarini M, Dodge GR, Eglin D, Guilak F, Madry H, Mata A, Mauck RL, Semino CE, Stoddart MJ (2013) Tissue engineering for articular cartilage repair--the state of the art. Eur Cell Mater 25: 248-267.
Loebel C, Czekanska EM, Bruderer M, Salzmann G, Alini M, Stoddart MJ (2015) In vitro osteogenic potential of human mesenchymal stem cells is predicted by Runx2/Sox9 ratio. Tissue Eng Part A 21: 115-123.
Sacchetti B, Funari A, Remoli C, Giannicola G, Kogler G, Liedtke S, Cossu G, Serafini M, Sampaolesi M, Tagliafico E, Tenedini E, Saggio I, Robey PG, Riminucci M, Bianco P (2016) No Identical "Mesenchymal Stem Cells" at Different Times and Sites: Human Committed Progenitors of Distinct Origin and Differentiation Potential Are Incorporated as Adventitial Cells in Microvessels. Stem Cell Reports 6: 897-913.
Selich A, Daudert J, Hass R, Philipp F, von Kaisenberg C, Paul G, Cornils K, Fehse B, Rittinghausen S, Schambach A, Rothe M (2016) Massive Clonal Selection and Transiently Contributing Clones During Expansion of Mesenchymal Stem Cell Cultures Revealed by Lentiviral RGB-Barcode Technology. Stem Cells Transl Med 5: 591-601.
The presented work has been supported by the AO Foundation and the Swiss National Science Foundation Grants 31003A_179438, 31003a_146375/1., 320000-116846/
14.0.2 - What about Regulatory Approval?
Progress of biologics in orthopaedic surgery, or orthobiologics, currently faces a delicate balance involving providers sprinting to apply clinically and profit on unproven technologies and the marathon of technology development through translational medicine. While early promising development of orthobiologics was in the hands of basic scientists, the next steps of translation require patient care and have stumbled upon regulatory hurdles and early clinical shortcomings, i.e. technologies not performing as well in clinical trials as they performed in laboratory and animal studies. These hurdles and shortcomings are part of the developmental process and should not be cause for concern. One can consider the study and understanding of FDA regulation a lot like understanding the rules of a sport. Rules have been made, precedent has been set, and we as clinicians should understand how to use the rules to not only judge emerging technologies but also to sort out how to use them in our clinical practice and clinical trials.
Orthobiologics to an orthopedic clinician represent any naturally derived product which can be used to improve the biology of healing in an orthopaedic intervention, including procedures in clinic such as joint injections and surgical procedures in the operating room. To the Federal Food and Drug Association (FDA), biological products are a subset of drugs and “biological” refers to those medical products which are derived from living material, as opposed to chemically synthesized (1). The FDA does not consider everything that clinicians consider orthobiologics as biological products. However, the FDA applies the Federal Food, Drug and Cosmetic Act (FDC Act) for the monitoring and regulation of many orthobiologics especially those involving cells.
Monitoring and regulation of orthobiologics is a double edge sword, important for patient safety and proof of worth on one side but stifling to progress at times on the other. Loose regulation encourages clinical experimentation, but raises concerns for patient safety, and does not force products to prove their value before clinicians set prices, market, and use them for patient treatments. Although rigid regulation stifles progress, it ensures patient safety and forces technologies to prove themselves through a developmental process. The latter requires a significant investment of time and money, but produces clear indications and evidence for care. Though there is not currently an answer (or agreement) to how much freedom or regulation should be established in the development of biologics, the following will be a discussion regarding where we are today, how we got here, and where are we headed. (2)
Progress of biologics in orthopaedic surgery faces a delicate balance of clinical application and technology development in the face of government regulations. While early development of orthobiologics was in the hands of basic scientists, the next steps will require the assistance of clinical researchers. Clinicians should understand how to use the governmental rules and regulations to judge emerging technologies and appropriately apply them to clinical practice and clinical trials. The Federal Food and Drug Association (FDA) is the United States governing body over the development and use of biologics in orthopaedic surgery. An understanding of the origin of the FDA and its current regulatory guidelines will help clinicians to avoid trouble from regulatory bodies and avoid malpractice risk when treating patients. This discussion of where we are today, how we got here, and where are we headed can be used to help further the work in the development and application of orthobiologics.
1 Frequently Asked Questions About Therapeutic Biological Products. In: Therapeutic Biologic Applications (BLA). 2017. Available at: https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/ucm113522.htm. Accessed July 10, 2017.
2 Anz, A.W., & Pinegar, C.O. (2018). FDA regulations and their impact. In A. Mazzocca & A. Lindsay (Eds.), Biologics in orthopaedic surgery (pp 9-17). St. Louis, MO: Elsevier.
14.0.3 - Do they have a Clinical Role in Joint Preservation?
The development and clinical application of expanded stem cells has been of huge interest in trauma and orthopaedics as a way to reverse bone and soft tissue injury with the delivery of these multipotent cells (1). Cartilage injury and subsequent osteoarthritis have significant social and economic implications for making them a research and treatment priority.
There has been a number of clinical studies investigating the treatment of chondral lesions using mainly bone marrow, synovial and fat derived expanded stem cells(2,3). There has been only a few comparative studies of MSC’s verses autologous chondrocytes and these have failed to demonstrate a significant difference(4,5). In comparison to chondrocytes, MSC’s are a very heterogenous population and potentially there is need for greater characterisation in order to identify the optimum “curative cell”. Alternatively, the concept of MSC and chondrocyte co-culture may direct better repair through paracrine signalling.
As a consequence of greater processing, the manufacture costs will increase and so greater clinical efficacy will be required in order to justify the health economic benefit. Based on the comparative early clinical experience and results relative to ACI, we need to look at strategies to reduce the manufacture costs if MSC’s are to be a viable treatment option in clinical practice. Potential stratergies could include:
Using minimally manipulated cells through an optimised one stage procedure
-A single stage procedure with a minimally manipulated cell product removes the need for an initial cell biopsy. By avoiding the significant regulation around Advanced Therapeutic Medicinal Products, the cost of product can be significantly reduced. There are a number of commercially available kits currently available for harvesting and concentrating bone marrow and fat cells. The vast majority of the clinical results within the literature are case series using Bone Marrow Concentrate(6) with only one animal study comparing BMAC to MSC’s. The current clinical evidence suggests there is therapeutic benefit to a single stage procedure. Further research is required to optimise processing in order to maximise cell harvesting and potentially cell characterisation.
The use of Allogenic cells
– Allogenic cells would enable a single stage procedure removing the need for an initial tissue biopsy. There is also the potential to treat many patients from a single tissue sample further reducing treatment costs(7).
Injection versus implantation
An injectable treatment would avoid the need for an invasive surgery and its associated costs to implant the cell treatment. Further potential savings could be made by removing the need for a scaffold to insert into the defect. Concern exists regarding the potential high rate of cell death following injection and whether cells will incite host repair at the site of the chondral lesion.(8)
Streamlined regulatory environment for cartilage related ATMP’s
All ATMP’s are currently managed under the same guidance, one which is similar to that used in the pharmaceutical industry. Due to the nature of chondral lesions and the associated pathology that commonly occurs (which excludes the majority of patients from clinical trials), bringing a new treatment can be very expensive and protracted. Modification of the current regulation would benefit the area of cartilage repair and accelerate future development
1. Cucchiarini M, Orth P, Rey-Rico A, Venkatesan JK, Madry H. Current perspectives in stem cell research for knee cartilage repair. Stem Cells Cloning Adv Appl. 2014 Jan;1.
2. Kim YS, Choi YJ, Lee SW, Kwon OR, Suh DS, Heo DB, Koh YG. Assessment of clinical and MRI outcomes after mesenchymal stem cell implantation in patients with knee osteoarthritis: a prospective study. Osteoarthritis Cartilage. 2016 Feb;24(2):237-45. doi: 10.1016/j.joca.2015.08.009. Epub 2015 Aug 28.
3. Kim YS, Choi YJ, Koh YG. Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes. Am J Sports Med. 2015 Sep;43(9):2293-301. doi: 10.1177/0363546515588317. Epub 2015 Jun 25.
4. Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH.Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. 2010 Jun;38(6):1110-6. doi: 10.1177/0363546509359067. Epub 2010 Apr 14.
5. Akgun I, Unlu MC, Erdal OA, Ogut T, Erturk M, Ovali E, Kantarci F, Caliskan G, Akgun Y. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg. 2015 Feb;135(2):251-263. doi: 10.1007/s00402-014-2136-z. Epub 2014 Dec 30.
6. Gobbi A, Whyte GP. Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate. Am J Sports Med. 2019 May 16:363546519845362. doi: 10.1177/0363546519845362.
7. de Windt TS, Vonk LA, Slaper-Cortenbach ICM, Nizak R, van Rijen MHP, Saris DBF. Allogeneic MSCs and Recycled Autologous Chondrons Mixed in a One-Stage Cartilage Cell Transplantion: A First-in-Man Trial in 35 Patients. Stem Cells. 2017 Aug;35(8):1984-1993. doi: 10.1002/stem.2657. Epub 2017 Jun 23.
8. Vega A, Martín-Ferrero MA, Del Canto F, Alberca M, García V, Munar A, Orozco L, Soler R, Fuertes JJ, Huguet M, Sánchez A, García-Sancho J.Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial. Transplantation. 2015 Aug;99(8):1681-90. doi: 10.1097/TP.0000000000000678.