L. Vonk (Teltow, DE)CO.DON Scientific Liaison
Presenter Of 5 Presentations
1.3.4 - Surgeon vs Scientist Gap - The Scientist Perspective
This presentation will focus on my scientist perspective during my post-doctoral research at the University Medical Center Utrecht, The Netherlands.
Part of my highlights consisted of providing academic “meet-the-patient” lectures and making other informative communications with patients1. These patients participated in an academic driven phase I / II clinical trial that investigated the safety and efficacy of a one-step combination of allogeneic mesenchymal stromal cells (MSCs) and autologous chondrons to treat cartilage defects (IMPACT - NCT02037204)2-4. A multidisciplinary team consisting of basic scientists, orthopaedic surgeon and researchers with experience in developing and manufacturing advanced therapy medicinal products (ATMPs) took this research from scratch through non- and pre-clinical research to clinical trials5-7.
In such a multidisciplinary team members speak a different language, have different needs and views and here it is very important to understand each other and to get everyone on the same page. In addition, as a basic scientist, coming from a background in molecular biology, you find yourself in a whole new kind of research area (translational and clinical research). I went from cloning genes to patient reported outcome scores and cost-effectiveness studies. One must want to put in the effort to get to know this new field and also be able to identify opportunities to improve the quality and findings of the research. I enjoyed every part of this challenging and succesful journey and learned so much; not only on doing other types of research but also others skills with a supervisor and other team members with a completely different background.
2 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 1;35(8):1984–93.
3 de Windt TS, Vonk LA, Slaper-Cortenbach ICM, van den Broek MPH, Nizak R, van Rijen MHPP, et al. Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single-Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons. Stem Cells. 2017 Jan 1;35(1):256–64.
4 Saris TFF, de Windt TS, Kester EC, Vonk LA, Custers RJH, Saris DBF. Five-Year Outcome of 1-Stage Cell-Based Cartilage Repair Using Recycled Autologous Chondrons and Allogenic Mesenchymal Stromal Cells: A First-in-Human Clinical Trial. Am J Sports Med. 2021;49(4):941–7.
5 Vonk LA, de Windt TS, Kragten AHM, Beekhuizen M, Mastbergen SC, Dhert WJA, et al. Enhanced cell-induced articular cartilage regeneration by chondrons; the influence of joint damage and harvest site. Osteoarthr Cartil. 2014 Nov 1;22(11):1910–7.
6 De Windt TS, Saris DBF, Slaper-Cortenbach ICM, Van Rijen MHP, Gawlitta D, Creemers LB, et al. Direct Cell–Cell Contact with Chondrocytes Is a Key Mechanism in Multipotent Mesenchymal Stromal Cell-Mediated Chondrogenesis. Tissue Eng Part A. 2015 Oct 1;21(19–20):2536–47.
7 Bekkers JEJ, Tsuchida AI, Van Rijen MHP, Vonk LA, Dhert WJA, Creemers LB, et al. Single-stage cell-based cartilage regeneration using a combination of chondrons and mesenchymal stromal cells: Comparison with microfracture. Am J Sports Med. 2013 Sep;41(9):2158–66.
As clearly mentioned in the content, this research was part of a multidisciplinary team and as part of that I would line to acknowledge Daniel Saris, Tommy de Windt, Ineke Slaper-Cortenbach, Jasmijn Korpershoek and Roel Custers
2.0.1 - Repair is not Good Enough?
Hyaline cartilage is a very specialised tissue; it´s main constituents are proteoglycans that attract and retain water and highly organized type II collagen fibers oriented in an arcade like structures. Due to this composition and confirmation, it can transmit mechanical forces and act as a shock absorber1. In addition, hyaline cartilage has a zonal orientation with the lamina splendens being the uppermost layer. The lamina splendens provides the smooth layer for the smooth movement of articular joints, it is very rich in lubricin and collagen fibers run parallel to the surface of articulation2. So, articular cartilage can function due to its composition and their confirmation. This leads to the question whether repairing a cartilage defect is good enough3.
Most of the currently used treatment procedures for cartilage defects do not provide a repair tissue that is similar to the native articular cartilage, or they come with other disadvantages.
For instance for microfracture it is well known that the repair tissue is more fibrocartilage-like that is rich in type I collagen instead of hyaline cartilage-like4. Although it provides satisfying outcomes on the short-term, the fibrocartilage cannot take over the function of hyaline cartilage and is more prone to degeneration on the long-term. Therefore, microfracture is only suitable for small defects and in larger defects the initial satisfactory outcomes can decline after a few years5. For larger (osteo)chondral defects autologous chondrocyte implantation or osteochondral allografts (if available) or other new upcoming treatments might provide a suitable treatment6-9. However, also these treatments do not provide 100% success. In addition, the question whether repair is good enough or not is also hampered by the lack of correlation between structural repair (MRI and / or histology) and patient reported outcome measures10. So even for a set of patients the tissue is repaired with a tissue that is similar to healthy cartilage, but there are still knee problems. On the other hand cartilage damage can be a surprise finding on imaging or during arthroscopy and be asymptomatic11.
1. Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: Structure, composition, and function. Sports Health. 2009;1(6):461–8.
2. Kumar P, Oka M, Toguchida J, Kobayashi M, Uchida E, Nakamura T, Tanaka K: Role of uppermost superficial surface layer of articular cartilage in the lubrication mechanism of joints. J Anat. 2001;199: 241-250.
3. Hunziker EB. The elusive path to cartilage regeneration. Adv Mater. 2009;21:3419–3424.
4. Steadman JR, Briggs KK, Rodrigo JJ, et al. Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up. Arthroscopy 2003;19:477-84.
5. Mithoefer K, McAdams T, Williams RJ, et al. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med. 2009;37:2053–2063.
6. Saris DBF, Vanlauwe J, Victor J, Almqvist KF, Verdonk R, Bellemans J. Treatment of Symptomatic Cartilage Defects of the Knee Characterized Chondrocyte Implantation Results in Better Clinical Outcome at 36 Months in a Randomized Trial Compared to Microfracture. Am J Sport Med. 2009;37:10–9.
7. Brittberg M, Recker D, Ilgenfritz J, Saris DBF. Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture: Five-Year Follow-up of a Prospective Randomized Trial. Am J Sports Med. 2018;46(6):1343–51.
8. Vonk LA, Roël G, Hernigou J, Kaps C, Hernigou P. Role of Matrix-Associated Autologous Chondrocyte Implantation with Spheroids in the Treatment of Large Chondral Defects in the Knee : A Systematic Review. Int J Mol Sci. 2021;22:7149.
9. Chahla J, Sweet MC, Okoroha KR, et al. Osteochondral Allograft Transplantation in the Patellofemoral Joint: A Systematic Review. Am J Sports Med. 2019;47(12):3009-3018.
10. De Windt TS, Welsch GH, Brittberg M, Vonk LA, Marlovits S, Trattnig S, et al. Is magnetic resonance imaging reliable in predicting clinical outcome after articular cartilage repair of the knee?: A systematic review and meta-analysis. Am J Sports Med. 2013;41:1695–702.
11. Horga LM, Hirschmann AC, Henckel J, et al. Prevalence of abnormal findings in 230 knees of asymptomatic adults using 3.0 T MRI. Skeletal Radiol. 2020;49(9):1099-1107.
13.1.3 - Nuts & Bolts of Grant Writing - What You Need to Know
Writing your first grant proposal can feel like throwing yourself in a shark tank; it is highly competitive, and you need a well written, scientifically sound with a founded budget proposal on an innovative idea to survive.
There are many different organisations and foundations where you can apply for grants and each of them have their own goals and vision, rules and application formats, but there are some common elements that will be discussed.
In general, you will always need to provide:
Abstract or summary:
Present the most important elements of each subchapter as short and as clear as possible. Always put in the problem statement, the aim of your proposal, the research questions and methodology, how to verify the success, why your project is important and why you or your consortium can do this.
Background and problem statement:
Particularly for academic proposals, a literature review on the topic can be very helpful. It states what is known and where the gap in knowledge is. It should show there is a need that must be filled. It should show the value of the proposal. in addition it should also clarify why the project will make an impact in stead of just answering a research question.
Project description or objectives and methodology:
Here you should describe the workplan of the project, answer questions as:
- what are the goals / what is the hypothesis?
- what are the research questions?
- what methods will be used to answer the research questions?
- what will the outcomes of the project be (SMART - specific, measurable, achievable, realistic and timely)?
- why are you sure the project will aid the problem statement?
- are there any risk minimizing measures and if so, which ones (sometimes this is a separate subchapter)?
- what is the timeline of the project? A Gantt chart can be very useful and helpful, also for the reviewers.
Here you need to clarify what budget you are asking for and why. You need to give an explanation or justification/specification of the materials, equipment and personell and why they are valid, reasonable and required.
whether it a personal grant or based on a consortium, it does need to show that the knowledge and experience is there to complete the project in a succesful way.
In addition to this, some grant application require letters of support or a cover letter.
Besides this, it is important to plan ahead and take plenty of time to write your proposal. Read through the call for proposals and make sure it is applicable for your project and it can help to add in specific topics found in the call to emphasize your proposal fits well. The writing must be very clear and in plain language, and be specific. Also use numbering as it provides a clear overview of a sommation and it can be used for easy cross-references. Make sure to always cite literature correctly and completely. Read through your proposal and ask someone else to do that too and also from the perspective of a reviewer. And do not fear rejection! All senior researchers have rejected proposals; even if your proposal is the best there is, it can be rejected due to other reasons. Always ask for feedback if it is not provided, read it through and learn from it.
24.1.9 - Meniscon: The ‘Chondron’ Extracted from Meniscus Tissue – Isolation, Structure and Culture
Learning to understand meniscus tissue has gained increasing attention. Cell to cell communication and metabolism modulation are essential components. We hypothesize that meniscus cells have a similar pericellular matrix as articular cartilage chondrons. The aim of this study was to investigate optimal isolation protocols, and identify the entity and composition of a meniscon. Furthermore, we want to explore the therapeutic potential of meniscons in meniscus tissue engineering and repair, similar to the use of chondrons for articular cartilage repair.
Methods and Materials
Cartilaginous tissue was obtained from patients undergoing total knee arthroplasty based on IRB-approved protocols. Finely minced meniscus and articular cartilage tissue were digested using two different protocols: 1. 0,3% (w/v) dispase(Gibco), 0,2% (w/v) collagenase-II in DMEM supplemented with 1% P/S (5-hours), 2. Rapid digestion using Liberase-MNP (45-minutes). Isolated meniscons and chondrons were mounted using cytocentrifugation and stained with Picrosirius Red and immunostained for type VI-collagen. TEM was performed to analyze cell morphology. To investigate zonal differences in meniscus, meniscons from inner and outer regions were isolated and compared for morphology and cell/meniscon ratios. Meniscons and meniscus cells were cultured up to 14 days in fibrin glue and analyzed using biochemical assays.
Meniscons and chondrons were successfully isolated using both protocols and stained positive for Picrosirius Red and type VI-collagen (Fig.1). For both chondron and meniscon, TEM shows the cell nucleus and membrane surrounded by the pericellular matrix (Fig.2). A significant higher ratio of meniscon/cell was observed for meniscons isolated from the inner meniscus vs the outer meniscus.
Similarly to chondrons, meniscons can be isolated from meniscus tissue using rapid digestion methods that yield meniscus cells plus their pericellular matrix. Chondrons have been used to improve repair of cartilage injuries. Similarly, meniscons could potentially be used in combination with current therapies, or by themselves, to enhance the repair of meniscus injuries.
Moderator Of 2 Sessions
- Participants will learn specific activities in cartilage treatment emphasized on German institutions and clinics.
Meeting Participant Of
Basic Science Committee Meeting
- M. Wimmer (Chicago, US)
- S. Nürnberger (Vienna, AT)
- C. Pascual Garrido (St. Louis, US)
- D. Haudenschild (Sacramento, US)
- J. Guicheux (Nantes, FR)
- L. Goodrich (Fort Collins, US)
- D. Evseenko (Los Angeles, US)
- A. Mobasheri (Vilnius, LT)
- L. Vonk (Teltow, DE)
- L. Gao (Homburg, DE)
- M. Sato (Isehara, JP)
- B. Grigolo (Bologna, IT)
- M. Stoddart (Davos Platz, CH)