Biomedical Engineering Reference
In-Depth Information
Chondrocyte Implantation' (CCI) utilizes a selected chondrocyte population that expresses a
marker profile that can predict cell ability to produce
in vivo
hyaline-like cartilage (Saris et
al., 2008). Many Authors in the Literature have suggested ACI effectiveness also for second
and third generation techniques and these procedures are now widely diffused and utilized
all over the world for cartilage defects repair. However, besides good outcomes evaluations,
there is still scepticism about the use of ACI, particularly for its clinical and cost
effectiveness in comparison with other traditional treatments and for the steeper learning
curve, at least compared with marrow-stimulating techniques (Vasiliadis & Wasiak, 2010).
Different Literature revisions highlighted that there is still insufficient evidence to draw
conclusions and that further trials with long-term follow up are required in order to clarify
ACI clinical benefits..
1.2 Cell manipulation in autologous chondrocyte implantation: from research to
cleanroom
Cell manipulation for ACI is crucial step that have to be performed in compliance with
GMPs in order to guarantee a safe, standardized and efficacious product to implant. In this
perspective the development of a validated and a repeatable process becomes a key issue for
this therapy. Chondrocytes can be easily isolated from articular cartilage tissue by
enzymatic treatments and then cultured in different conditions like monolayer, bi/three-
dimension, chemical or mechanical stimulation or inhibition. Several chondrocyte culture
systems that have been developed display a huge number of applications in the research
field as attested by worldwide publications. In fact they represent models for cartilage
investigation, which is essential for identifying the pathways of both normal development
and pathological degeneration and inflammation of the tissue (Roseti et al., 2007). Recently,
there has been a great deal of interest in the
ex vivo
development of hyaline cartilage that can
be utilized for the regeneration of damaged or diseased tissue. The realization that
chondrocytes may act as drugs having therapeutical effects in cartilage regeneration led to
new responsibilities and roles for cell culture's laboratory. ACI application required an
integration work between clinicians and cell biology experts and it would not have been
possible without the support of GMPs specialized laboratories or facilities. Obviously,
clinical application of research models presents specific features of quality assurance which
must be met. In particular, for cell cultures, a transfer technology step is required or, in other
words, research protocols must be translated into GMPs' ones. This involves taking into
account not only the peculiar nature of cells and culture's models, but also the mandatory
compliance with current GMPs and all the specific cell therapy regulations. This chapter
describes the transfer technology utilized to standardize the manufacturing of engineered
chondrocyte-based products for applications in ACI. In particular, it focuses on the
development and validation of a GMPs' compliant manufacturing process and then of
“consistent” chondrocyte-based medicinal products. The GMP facility performing the below
described validation processes is located in a public Hospital in Italy. Therefore specific
Italian and European rules have been followed.
2. Development and validation of a GMPs compliant chondrocyte culture
process suitable for clinical use
Process validation is a pre-requisite to ensure consistent manufacture. Cell processing such
as in ACI is a long lasting, articulated process. It comprises three main manipulation phases
