CRP Meeting 2015

ARI's Annual Collaborative Research Program (CRP) Meeting was held in Philadelphia, US from September 14–16, 2015

28 October 2015

AFR partners and committee during breakout session

​The Meeting started with a welcome address from Prof R Geoff Richards, director of the AO Research Institute Davos, followed by progress reports from the CRP research partners, post-presentation discussions, and breakout sessions.

CRP Annulus Fibrosus Rupture (AFR) Session 

The CRP AFR session was moderated by Prof Gunnar Andersson (Rush University, US) and Prof Peter Roughley (Shriners Hospital for Children, CA); both are members of the CRP AFR advisory Committee. The session commenced with an overview presentation by Dr Sibylle Grad (ARI, CH) summarizing the program, goals and the roles of the individual program partners in the final proof of concept (PoC) study. The final aim of the Program is to develop a functional implant for the repair of annulus fibrosus defects by using biomaterials and bioactive agents specifically designed by the consortium partners. This overview was followed by the talk of Prof Dirk Grijpma (University of Twente, NL) who presented an update on the design and optimization of his flexible PTMC scaffolds used to seal AF defects. These scaffolds can be tuned in terms of porosity, pore size and degradation behavior in order to minimize the risk of extrusion. Prof James Iatridis (Mount Sinai School of Medicine, US) then reported on their adhesive biomaterial which is applied as a sealant for restoring disc mechanics and promoting repair of the ruptured annulus. The fibrin-genipin adhesive glue has been shown to promote repair of large annular defects in organ cultures and is currently also being investigated as drug or cell carrier.

Subsequently Dr David Eglin (ARI, CH) presented an update on his poly(ester-urethane) membrane used for the closure of the annulus fibrosus defect; in addition, new methods to reinforce the cohesion of the adhesive sealant using polymeric fibers were introduced. This reinforcement significantly improved the adhesion strength of the sealant. Prof Stephen Ferguson (ETH Zurich, CH) then reported on his proof testing of the implant coatings and the biomechanical verification of implant performance. Biological modification of e-spun membranes significantly inhibited cell adhesion, which will be essential to prevent dural adhesion / neural ingrowth. Furthermore, baseline biomechanical tests for ovine lumbar and cervical discs are ongoing in order to establish an optimized procedure for the PoC study analysis. Prof Ferguson's presentation was followed by an update on the delivery system of bioactive hyaluronan microgels for reducing the inflammatory reaction in the ruptured annulus developed by Prof Abhay Pandit (National University of Ireland, IE). In an organ culture annular defect model with induced inflammation, delivery of hyaluronan microgels showed significant anti-inflammatory and anti-catabolic effects.

After that Prof Daisuke Sakai (Tokai University, JP) provided a final report on the implantation of the consortium biomaterials in the rat tail annulus defect model. Neither the PTMC scaffold nor the polyurethane membrane showed signs of degradation after up to 16 weeks; while the fibrin-genipin glue was mostly degraded after 16 weeks. Then he spoke on the generation of functional annulus fibrosus cells for the PoC study and for human applications. Specifically, a highly proliferative cell population with improved ability for cell contraction in collagen was described. Dr Stephan Zeiter (ARI, CH) presented the concluding report for the morning session updating the participants on the results obtained with the sheep pilot studies and the progress made with the sheep proof of concept studies in which the developed device is being tested. Two pilot studies were performed, using different combinations of fibrin-genipin glue, PTMC scaffold, and polyurethane closure membrane in lumbar and cervical AF defect models. For the main studies the consortium decided in favor of the cervical disc full thickness AF defect model, due to the larger disc height, better accessibility and better reproducibility of the procedure. While one sheep study that used the adhesive glue injected in the defect is currently ongoing, the decision on the "bioactive" implant will be made according to the results of further pilot and organ culture experiments.

Prof Gunnar Anderson and Prof Peter Roughley thanked the presenters for their detailed progress reports and all participants for their active contributions during the post-presentation discussions which are an integral part of the Annual Meeting. They also highlighted issues especially related to the proof of concept study that would require further in depth discussions at the CRP AFR breakout session on the next day.

CRP Acute Cartilage Injury (ACI) Session

In the afternoon CRP ACI session was moderated by Prof Mats Brittberg (Kungsbacka Hospital, SE)  and Prof Brian Johnstone (Oregon Health Science University, US) who together with Prof Peter Roughley (Shriners Hospital for Children, CA) are the expert members of the CRP ACI advisory Committee.

The session commenced with an overview presentation by Dr Martin Stoddart (ARI, CH) summarizing the program goal to screen various macroporous materials, hydrogels, viral vectors and cell sources for cartilage repair, resulting in a final combination that can be investigated in a cartilage defect proof of concept study (PoC). The  final PoC will investigate a woven macroporous polycaprolactone scaffold in various combinations with a hyaluronic acid based hydrogel (ARI) or a self-assembling peptide hydrogel (Barcelona, Spain). A further stimulus from an adeno-associated virus (AAV) overexpressing the cartilage transcription factor Sox9 will also be included.

Prof Farshid Guilak (Duke University, US) and Dr David Eglin (ARI, CH) then provided an update on the hard (woven macroporous polycaprolactone) and soft (hyaluronic acid based hydrogel) and self-assembling peptide hydrogel) materials chosen to be used within the final PoC. These materials were chosen from the large initial pool of combinations due to their promotion of chondrogenesis. Prof Henning Madry (University of Saarland, DE) presented the AAV vector that over expresses Sox9 and showed some of the improved chondrogenesis observed in Göttingen minipig studies focused on genetically modified implants. This was followed by an update on the Yucatan minipig PoC study and the post-mortem examination plans provided by Prof Rob Mauck and Dr George Dodge (University of Pennsylvania, US). The potential to confirm implant retention using arthroscopy was demonstrated. After a short coffee break, each of the methodologies to be implemented in the final PoC study were described in detail. Initially, Prof Henning Madry described the surgical approach, followed by a discussion on arthroscopy led by Dr George Dodge. A description of morphological assessment was then provided by Prof Henning Madry. The final post mortem assessments were explained by Prof Rob Mauck (indentation testing), Prof Farshid Guilak (MRI) and Dr George Dodge (histological evaluation). An active discussion was then moderated by Dr Martin Stoddart to obtain final comments from all present.

Prof Peter Roughley and Prof Mats Brittberg thanked the presenters and participants for their valuable input and their discussion contributions. They were highly impressed with the focused nature of the final application with the final details of the PoC study being prepared during the CRP ACI breakout session on the following day.

CRP ACI and AFR Breakout Sessions

The CRP breakout sessions took place in the morning of the second day. These sessions are crucial for the consortium partners and the program deliverables, as they provide the opportunity for face-to-face discussions of the partners with the program committee experts. Since the last phase of the program involves an in vivo PoC study with the developed device with both consortia, most of the discussions were related to this topic. Especially interactions among partners and the detailed research plan to meet the milestones for the following year were reviewed in discussion with the committee and finalized at this session.

In the afternoon the partners were invited by Prof Rob Mauck and George Dodge on a tour and poster session at the Translational Research Center and the McKay Laboratory at the University of Pennsylvania. The day was concluded with a visit to the famous Barnes Foundation, which was a particular highlight. This was followed by a dinner with all meeting participants.

Visit to Partner Site in New York

On the final day the CRP AFR team travelled to New York to the Mount Sinai Orthopedic Research Laboratories at the Icahn school of Medicine. Prof James Iatridis and his team took them on a fascinating tour through his laboratories and presented a comprehensive overview of their research activities.

Feedback from Participants & Outlook

The feedback on the Annual CRP Meeting 2015 was overwhelmingly positive. This is illustrated by emails received from the participants after the meeting: Prof Farshid Guilak: "Just wanted to thank AO/ARI as well as Rob and George for organizing such a great meeting. Not just for the usual excellent science and teamwork that is a hallmark of this group, but also for the wonderful hospitality and social events with an amazing group of friends." Prof Joost de Bruijn from the AO Research Institute Davos Advisory Committee (University of Twente, NL): "As AO Research Institute Davos advisor and somewhat of an outsider to your groups, I am impressed with the good scientific discussions, collegiality and friendship that exist within the AFR and ACI teams." Last but not least, Prof James Iatridis: "This is a wonderful, productive, and efficient scientific collaboration and the annual meeting is one of the highlights for my year".

Most of the partners are planning to meet again and discuss progress, at the next ORS Meeting in March 2016 in Orlando, US.



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