Project: High yield cartilage cell isolation for commercially viable, single surgery knee cartilage repair

Background_x000D__x000D_Articular cartilage damage within the knee joint is a leading cause of disability in Europe and elsewhere with 1,200,000 patients diagnosed annually. Unfortunately, cartilage defects do not repair naturally and, if untreated, frequently develop to osteoarthritis. All current treatments suffer from major disadvantages. Cartilage repair is therefore often referred to as the holy grail of orthopaedics. _x000D__x000D_While autologous (patients own) cartilage cell (chondrocyte) based treatments (ACI, autologous chondrocyte implantation) have been demonstrated to be clinically effective, they are costly and complex two surgery procedures which have failed to gain any commercial traction (less then 1% of all patients receive ACI). This is due to the inherent need for labour intensive ex vivo cell culture expansion requiring a complex two step procedure. Furthermore, cellular quality is negatively affected by cell expansion. During cell culture expansion, the isolated spherical (differentiated) chondrocytes lose their cartilage forming capacity, and become elongated fibroblastic cells (they de-differentiate). While re-differentiation occurs post implantation in situ, it takes time (usually many months), and it does not occur for all patients. _x000D__x000D_To overcome the drawbacks of ACI, one of the applicants has recently developed a cartilage repair approach which eliminates chondrocyte expansion altogether by replacing it with a cell combination (into a one step procedure, currently in clinical (safety) trials). The essence of the therapy is the processing of patients own chondrocytes and bone marrow (mono nucleated) cells into a biomimetic scaffold for implantation into the defected cartilage void, in combination with a novel rapid chondrocyte isolation method, all within the same surgery. We have previously demonstrated that this cell combination substantially and significantly improves cartilage formation in vitro and in vivo, through a cell synergy mechanism (based thereon the therapy has been named INSTRUCT). A number of publications (more than 10) have verified this, while CellCoTec owns the IP (granted in the EU). Moreover, INSTRUCT has been classified as a medical device by the UK and Belgian authorities, and the FDA, thereby simplifying regulatory requirements and shortening time to market._x000D__x000D_However, currently only a small fraction of the chondrocytes present in cartilage tissue can be isolated as viable cells (20% and, possibly not the most potent in cartilage repair capacity, Jakob et al 2003, one of the applicants). Accordingly, the vast majority of cells, 80%, are unavailable for repair purposes (due to severe cell damage during the current isolation) while the amount of cartilage which can be harvested from the patient's knee cartilage is limited (about 300 mg, harvested from a less weight bearing region of the joint cartilage)._x000D__x000D_Clinical efficacy of cell based therapies depends on chondrocyte number, and INSTRUCT is no exception._x000D__x000D_Accordingly, chondrocyte isolation yield (and time, being connected to yield and, determining surgery time) is at the core of the clinical and commercial potential of INSTRUCT._x000D__x000D_Goals and applications_x000D__x000D_Therefore , this project aims to develop i) a novel high yield method for chondrocyte isolation, (technical process, IP), ii) implement it into a single surgery yet autologous cell based cartilage repair therapy (INSTRUCT) in order to maximize clinically effectiveness and commercial viability (product for clinical efficacy testing following this project, anticipated annual sales of € 47 million in 2017), and iii) improve the understanding of the molecular processes during chondrocyte isolation (data for further optimization)._x000D__x000D_This will be achieved by using small and inexpensive molecules (an osmolarity modulator, and, an antioxidant) for which POC has been demonstrated by one of the applicants (up to 100% and up to 40% increase in cell yield if applied separately, respectively). These will be combined with a novel rapid cartilage dissection method (POC available) in combination with well known digestive enzymes (i.e. collagenase). Based on the above POC data, we consider a 200% (3x) target increase compared to current state of the art as achievable (equivalent to the majority (60%) of chondrocytes within cartilage isolated as viable cells). If achieved, the majority of the cells would be available for repair purposes rather than wasted, as currently._x000D__x000D_Project consortium_x000D__x000D_To reach this goal, CellCoTec, a development stage ISO 13485 certified orthopedics SME (coordinator), and University Hospital Basel (UBasel), will join their unique and complementary expertise in single surgery cartilage repair (CellCoTec), chondrocyte isolation (UBasel) and rapid chondrocyte isolation (CellCoTec), chondrocyte biology (UBasel), product development (CellCoTec), and clinical aspects (UBasel). The Ps have previously collaborated on two successfully completed projects (Eureka and Marie Curie)._x000D__x000D_

Acronym IsoCart (Reference Number: 6065)
Duration 01/03/2011 - 31/10/2013
Project Topic Cartilage cells are the basis for clinically effective knee cartilage repair. Currently, only 20% can be isolated as viable cells from cartilage tissue. This project will establish a new method to liberate 60% of viable cartilage cells and implement it into a single surgery cartilage repair therapy.
Project Results
(after finalisation)
Addition of the following factors during the cell isolation phase resulted in the following:_x000D_* Increased osmolarity facilitates in increased chondrocyte cell yield (up to 92%), although success rate very donor depending)_x000D_* ASAP (Vitamin C) is also highly donor depending but leading to an increase of chondrocyte isolation (117-160%)_x000D_* Combination of increased osmolarity plus ASAP didn't show additional benifit_x000D_* Addition of Calcium also increase isolation cell yield (10-25%)
Network Eurostars
Call Eurostars Cut-Off 5

Project partner

Number Name Role Country
2 CellCoTec BV Coordinator Netherlands
2 University Hospital Basel Partner Switzerland