In Rizzoli Orthopedic Institute a long regenerative medicine tradition is established. Among all countless projects ongoing in the Institute, the hospital joins the regenerative clinical arena with 3 big national and international initiatives: project Orthounion, an innovative approach to manage non-consolidated fractures, based on autotransplantation of GMP expanded bone marrow mesenchymal stem cells; Italian Regenerative Medicine Infrastructure (IRMI), public-private national network with the mission to push innovation and increase international competitiveness of Italian industries and institutes; Rizzoli Cell Factory, the first public department in Italy implementing a Class A clean room-based facility, which is today reshaping its operative models with innovative technologies that will grant more productivity and more dynamicity in developing innovative therapies. Project web site: www.custom-implants.it Presentations and videos: cerr.eu/what-s-going-on/357-materiali-dei-seminari-disponibili-online Further materials: www.slideshare.net/CERRicerca

1. Regenerative medicine in Orthopedics:
experience of the Rizzoli Orthopedic
Institute and perspectives
Turin, 12-10-2017
Nicola Fazio

2. Regenerative medicine is the branch of medicine that
develops methods to regrow, repair or replace
damaged cells, organs or tissues.
Regenerative medicine includes the generation and
use of therapeutic stem cells, tissue engineering and
the production of artificial organs.
Nature

3. Aim of Regenerative Medicine is to cure and
not to chronicize the diseases.
This way to approach diseases has both social
and economic consequences

4. A couple of example of CHRONICIZED
disease that represent a huge burden
for Health Systems

7. increase in average life
expectancy
In 2020 for the first time in
human history the number of
people over 65 will exceed the
number of children under the
age of 5 with an inevitable
increase of age-related diseases
PRESENT
CLOSE FUTURE
Today the improvement of care
standards
led to an

9. In Rizzoli Orthopedic Institute a long regenerative
medicine tradition is established. Among all countless
projects ongoing in the Institute, the hospital joins
the regenerative clinical arena with 3 big national and
international initiatives:
- Orthounion
- IRMI
- Cell Factory
A rapid glance to this projects!

11. Fractures of the long bones
are especially prone to
nonunion in close to 15% of
such fractures. This can
result in significant
morbidity and represents an
economic burden.
The standard of care of non-
unions fractures is the Iliac
Crest AUTOTRANSPLANTATION,
technique with high morbidity
to patients

12. ORTHOUNION is a multicentre, multinational, randomized
clinical trial aimed at testing the superiority of an innovative
Advanced Therapy product versus the Iliac Crest
Autotransplantation in long bone non-unions.
ORTHOUNION was funded with 6 M € in the frame of H2020
research and innovation programme and is the natural
progression of previous FP7 REBORNE project

13. Cell Factory
MBCP+
BMSC+MBCP+
The ORTHOUNION Clinical Trial consists in the transplantation
of autologous BMSC, GMP cultured in a Cell Factory and
combined during surgery with a commercial Ceramic
Biomaterial (Macroporous Biphasic Calcium Phosphate,
MBCP+) to fill the non-union site under surgical procedure.

14. ORTHOUNION consortium comprises 11 partners and 3
linked third parties, including 20 clinical centres and 5
cell production units, from France, Germany, Italy (IOR,
UNIMORE and Policlinico di Milano) and Spain.

15. The study will include around 100 patients divided in 3
groups, named CONTROL, Low-Dose BMSCs and High-
Dose BMSCs, to study also if and how the number of
transplanted cells influences the healing process.

16. More detailed information available on
the website:
https://orthounion.eu/

18. The European Commission and the European
Strategy Forum on Research Infrastructures (ESFRI)
define “Research Infrastructure” as follow:
A structure or platform able to provide scientific community with resources and services to
help performing high level researches in their respective operative field.
Such Research Infrastructures can be located in a single site or dislocated, can be part of a
National or International network and MUST:
- Offer services and supports of excellence scientific quality;
- Allow access to scientits, Academia and Industry through a trasparent selection;
- Possess a stable and efficient mangement model

19. Europe considers Research Infrastructures as a key
instrument in attracting and bringing together researchers,
funding agencies, politicians and industry to act together
and tackle the cross-disciplinary issues of critical importance
for our continued prosperity and quality of life.

20. With this in mind, within the frame of Ministry of
Instruction University and Research (MIUR),
Italian National Cluster Iniative
We developed the
Italian Regenerative Medicine Infrastructure (IRMI)
Within the health National Cluster ALISEI

21. IRMI is an Infrastructure of Italian stakeholders operating in
the regenerative medicine sector with the aim of:
1) potentiating Italian biobanks and cell factories network;
2) supporting research and industrial development of
ATMP;
3) pushing national innovation in the field, increasing
international competitiveness of Italian industries and
public institutes;
4) creating new training courses for new professional
figures in the various articulations of regenerative
medicine;
5) promoting rigorously scientific public dissemination
activities about true principles and potential of
regenerative medicine.

22. IRMI
14 Research Centers
Istituto Ortopedico Rizzoli
Università di Modena e Reggio Emilia
Università di Bologna
Università di Milano
CNR Roma
CNR Napoli
Università di Torino
Politecnico di Torino
Università di Genova
Università di Trieste BIOMAT
RiMED
Università Tor Vergata
Tecnopolo Castel Romano
7 Industries
Gruppo GVM (project leader)
AB Medica
Genomnia
Chiesi Farmaceutici
AB Tremila
Holostem
IGEA
Dislocated in 8 Italian
Region
Lombardia
Piemonte
Emilia-Romagna
Lazio
Sicilia
Friuli Venezia Giulia
Liguria
Campania
Today main composition of the infrastructure is the
following:

23. Besides the Infrastructures activities, all the partners
have specifics scientific projects to be achieved.
For what it concerns Rizzoli Orthopedic Institute,
following products are being developed in the frame of
IRMI project:
- GMP-Expanded Autologous Fibrocytes seeded on 3D
scaffolds or in suspension to treat chronic ulcers and
skin burns;
- A new generation of osteoinductive pastes;
- An innovative one-step technique to separate ASCs
from lipoaspirate;
- New alloplastic custom implants;

24. Being the first Italian Infrastructure on
Regenerative Medicine, IRMI will try in next
future to increase its leading role also in
Europe, including other stakeholders and
participating in the incoming Research
Infrastructures H2020 calls

25. More detailed information available on
the website:
http://www.irmi.eu/

27. All the cell-based therapies produced by
a cell factory are considered Advanced
Therapy (ATMP) and they require
authorization from competent authority
(AIFA)
This authorization is bond to
implementation of a GMP facility

28. The Rizzoli Cell Factory was
established in 2006, being the first
public department in Italy
implementing a Class A clean room-
based facility.
In those years the most advanced
aseptic environment technology was
the Clean Room

29. The first GMP facility was then
based on clean room technology

30. Traditional Cleanroom Technology
Manufacturing in Clean Room
Environmental
Monitoring
Sanitization
Open LAF
Gowning
High Volume of
Handled Air
Basically when you work in a clean
room is like if you physically were
inside a sterile hood!
You can’t manipulate a second lot
before a special and expensive
sanitization
With this technology, Cell Factory
was able to produce 25 lots of
autologous chondrocytes every
year.
We believe that clean room
technology is much more suitable
for larger scale production

31. TODAY NEW GMP-
COMPLIANT TECHNOLOGIES
ARE AVAILABLE

32. After 6 years of experience of cartilage regenerative
therapies, the Rizzoli Cell Factory is today reshaping its
operative models by implementing innovative technologies,
based on GMP-grade isolators.

33. We believe that GMP-grade isolators possess
several features that will help us in increasing
productivity, dynamicity in the development of
innovative orthopedic therapies and the the
number of assisted patients

34. The new Rizzoli Cell Factory will be implemented with
two GMP-grade isolators placed inside two separated
Class C environments surrounded by background D
With this technology we forecasted to assist an
average of 60 patients every year.

35. Basing on the first described experiences
Chondrocytes/IRMI/Orthounion
First products to be developed will be:
- Autologous Chondrocites;
- Autologous BMSCs for bone non-union;
- Autologous Fibroblasts to treat chronic ulcers and
skin burns
……but not only!!!!!!!!!!

36. We also think that an efficient Cell Factory has the precious potential
to serve as referring HUB, providing outsource services such as:
So not only a place where cell products are manufactured,
but an excellence structure where clinical researcher can
refer to develop innovative Advanced Therapies toghether.

37. Thank you!