ST. CATHERINE HOSPITAL IS “THE CENTER OF EXCELLENCE” FOR CARTILAGE DEFECT TREATMENT WITH MESENCHYMAL STEM CELLS
This procedure was launched in St. Catherine Hospital in November 2015.
Application of Mesenchymal stem cells therapy
The use of adipose tissue has taken on increasing importance in the field of regenerative stem cell therapy. This therapy can be divided into two major pathways. One pathway involves plastic and reconstruction surgery. The other major pathway involves orthopedics and its related fields. New therapeutic approaches, such as the use of mesenchymal stem cells (MSC), seem to show promising preliminary results when applied in the context of joint degeneration and osteoarthritis. MSCs were first reported by A. Caplan in 1991. MSCs have extensive proliferative ability in culture in an uncommitted state, while retaining their multilineage differentiation potential, which makes them attractive candidates for biological cell-based tissue repair approaches. The controversial and often poorly understood roles of MSCs are slowly being elucidated and the regenerative capabilities of fat (adipose derived stem cells, ADSCs), with mesenchymal properties, are being widely explored. Through trophic, mitogenic, anti-scarring, anti-apoptotic, immunomodulatory, and anti-microbial actions, produced by a plethora of bioactive elements, growth factors and cytokines, these cells “sense” and “signal” changes in the microenvironment where they reside. More recently, perivascular cells (pericytes) have been reported as the originators of MSCs. Adipose tissue is rich in vascular niches, that provide a readily available source of native cushioning, and could serve as a source of potential healing and regenerative tissue containing ADSCs.
Fat Tissue Potential
The idea that fat tissue is an optimal source of mesenchymal stem cells (MSC), is supported by the abundance of these cells in this tissue compared with other tissues, such as the widely-used bone marrow, and by their easy access. Indeed, 1 in 100 adipose tissue cells is a mesenchymal stem cells (MSC), compared with 1 in 100,000 bone marrow cells. Moreover, bone marrow harvesting is an invasive and traumatic procedure compared with lipoaspiration and is performed under general anesthesia with a higher risk of viral infection. Finally, it is widely recognized that the viability and differentiation capacity of bone marrow-derived mesenchymal stem cells (MSC) decreases with increasing donor age. Fat tissue is available in large quantities in most patients and can be harvested easily with a minimally invasive approach (under either local or general anesthesia), offering a highly viable mesenchymal stem cells (MSC) population with optimal differentiation potential independent of the donor’s age. The regenerative potential of adipose tissue-derived mesenchymal stem cells (MSC) is similar to that reported in other tissues (1).
The Lipogems® technology
The Lipogems® technology, patented in 2010 and clinically available since 2013 (PCT/IB2011/052204), represent a new completely closed tool to harvest, wash, process, and reinject human (or animal) lipoaspirates. Briefly, the surgical procedure consists in two steps: the infiltration step, in which adrenalin, in a saline solution, and very diluted lidocaine are injected to induce vasoconstriction and local anesthesia, facilitating the subsequent lipoaspiration; the aspiration step, in which a standard liposuction technique is performed (2). In short, the Lipogems® technology is characterized by optimal handling ability and a great regenerative potential based on adipose-derived mesenchymal stem cells (MSC).
Lipogems® recently obtained FDA clearance. In this novel technology, the adipose tissue is washed, emulsified, and rinsed and adipose cluster dimensions gradually are reduced to about 0.3 to 0.8 mm. In the resulting Lipogems® product, pericytes are retained within an intact stromal vascular niche and are ready to interact with the recipient tissue after transplantation, thereby becoming mesenchymal stem cells (MSC) and starting the regenerative process. (1)
How is fat obtained
The fat used for the transfer can be taken from any area of the body, although the abdomen is preferred. Dilute local anaesthetic is injected into the donor area, than the fat is obtained using a special needle.
Mechanism of action
Theories related to the potential mechanism of action may include the micro-fragmented adipose tissue providing volume, support, cushioning, filling of soft tissue defects or potential healing and regenerative capabilities. Additional mechanisms may include direct differentiation and chondrogenesis, regenerative signaling by activated perivascular cells, tissue repair, signaling of trophic and paracrine factors, activation of opioid receptors, pain reduction, down-regulation of the arthrogenic muscle inhibition, exosome initiated cascades or a combination of all of these. In the resulting Lipogems® product, pericytes are retained within an intact stromal vascular niche and are ready to interact with the recipient tissue after transplantation, thereby becoming MSCs and starting the regenerative process (1).
Recent work on Ceserani indicate that Lipogems® micro-fragmented adipose tissue retains either per se, or in its embedded MSCs content, the capacity to induce vascular stabilization and to inhibit several macrophage functions involved in inflammation (3).
However, promising in vitro assays results (4) where the potential of intra-articular injection of micro-fragmented lipoaspirate was investigated, it may be speculated that an injectable autologous biologically-active scaffold (lipoaspirate), employed intra-articularly, may either:
1 - become a fibrous tissue that provides mechanical support for the load on the damaged cartilage;
2 - induce host chondrocytes to proliferate and produce ECM;
3 - provide cells at the site of injury, which could regenerate or repair the damaged or missing cartilage.
Lipogems® Clinical Application
Lipogems® has proved to be very effective mainly in clinical regenerative cases, although adequate scientific support from formal clinical trials is needed to confirm these promising results.
The very low infection risk is a result of the production of the antimicrobial molecule LL-37 (1). Based on clinical results from more than 800 patients worldwide (obtained from many European and American colleagues), the intra-articular injection of Lipogems® to treat knee, ankle, hip, and shoulder osteoarthritis resulted in a surprising improvement in symptoms, with 100 % safety of the procedure. In addition, single-case reports have demonstrated that intra-articular injection of Lipogems® in patients with osteoarthritis and nonresponsive knee pain in association with meniscal damage seems to improve joint functionality (5) and recently it was published that intra-articular injection of Lipogems® improved knee function in a patient with a posttraumatic lesion of the cartilage (5). The improvement in measured outcomes for pain, quality of life, KOOS (Knee Injury and Osteoarthritis Outcome Score), and MRI imaging showing sustained gains up to 6 months (6).
Professor C. Zorzi and dr. A Russo from Sacro Cuore-Don Calabria Hospital, Verona, Italy recently reported results on 170 patients affected by knee chondropathy to whom a single intra-articular injection of Lipogems® was applied. They concluded that despite of the heterogenity of the population, the trend is of significant improvement. Out of 170 patients they reported only two adverse events (abdominal hematoma).
Professor Joseph Purita, Director of the Institute of Regenerative and Molecular Orthopaedics in Boca Raton, Florida who is among pioneers in the use of stem cells and platelet rich plasma PRP), highlighted that the Lipogems® technique so far has been utilized in over 5,000 patients.
In our recent study, 16 patients (30 knees) were examined at baseline and at 3, 6 and 12 months after Ad-MSC application. Our data suggesting that the use of adipose derived mesenchymal stromal/stem cells (Ad-MSC) therapy in patients with osteoarthritis result (measured by dGEMRIC MRI) increased glycosaminoglycans (GAGs) content deposition in hyaline cartilage. Those results are in line with secondary outcome measurements including quantitative MRI analysis, KOOS and VAS.
However, now, several clinical trials are under way to support the initial encouraging outcomes. Lipogems® is a minimal risk procedure: in fact, it would be considered the safest technique of this kind.
1.Tremolada, C., Colombo, V. & Ventura, C. Adipose Tissue and Mesenchymal Stem Cells: State of the Art and Lipogems® Technology Development. Curr Stem Cell Rep. 2016;2:304-312. doi:10.1007/s40778-016-0053-5.
2. Tremolada C, Beltrami G, Magri A, Bianchi F, Ventura C, Di Vito C, Campanella R, Navone SE, Marfia G, Caplan IA. Adipose Mesenchymal Stem Cells and “Regenerative Adipose Tissue Graft” (Lipogems) For Musculoskeletal Regeneration. European Journal of Musculoskeletal Diseases. 2014;3(2): 57-67.
3. Ceserani V, Ferri A, Berenzi A, Benetti A, Ciusani E, Pascucci L, Bazzucchi C, Cocce V, Bonomi A, Pessina A, Ghezzi E, Zeira O, Ceccarelli P, Versari S, Tremolada C, Alessandri G. Angiogenic and anti-inflammatory properties of micro-fragmented fat tissue and its derived mesenchymal stromal cells. Vascular Cell. 2016;8:3. doi: 10.1186/s13221-016-0037-3.
4.Bosetti M, Borrone A, Follenzi A, Messaggio F, Tremolada C, Cannas M. Human Lipoaspirate as Autologous Injectable Active Scaffold for One-Step Repair of Cartilage Defects. Cell Transplantation. 2016; 25:1043–1056.
5.Striano R, Chen H, Bilbool N, Azatullah K, Hilado J, Horan K. Non-responsive knee pain with osteoarthritis and concurrent meniscal disease treated with autologous micro-fragmented adipose tissue under continuous ultrasound guidance. CellR4. 2015; 3 (5): e1690.
6. Franceschini M, Castellaneta C, Mineo G. Injection of autologous micro-fragmented adipose tissue for the treatment of post traumatic degenerative lesion of knee cartilage: a case report. CellR4. 2016; 4 (1): e1765.
7. Hudetz D, Borić I, Rod E, Jeleč Ž, Radić A, Vrdoljak T, Skelin A, Lauc G, Trbojević Akmačić I Plećko M, Polašek O, Primorac D. A year follow-up study of Ad MSC therapy in patients with knee osteoarthritis. Book of Abstracts. The Tenth ISABS Conference on Forensic and Anthropologic Genetics and Mayo Clinic Lectures in Individualized Medicine. Dubrovnik, June 19-24, 2017.