Ranieri Cancedda, Beatrice Dozin, Paolo Giannoni, and Rodolfo Quarto: Tissue engineering and cell therapy of cartilage and bone
Canceda et al. provides a comprehensive practical and biochemical analysis and evaluation of different treatments for bone and cartilage lesions, as well as providing sufficient background information about the biology of appropriate cells and tissues relevant to the discussion. The apparent motive for this paper is the widespread cartilage and bone damage and their increase vulnerability with age, and the challenges current treatment methods pose to clinicians.
The field or regenerative medicine aims at using innate regenerative biochemical pathways to heal damaged tissue. Different tissues have different regenerative potentials. Bone tissue is much more prone to regeneration than cartilage because of its continuously changing morphology through the lifetime of an organism. These differences lead to different types of treatment for the lesions, depending on their area of infliction.
Common surgical treatment for joint damage are microfracturing, autologous osteochondral transfer (mosaicplasty), and fresh osteochondral allograft. However, these procedures are limited by donor characteristics like number, compatibility, and by skill level the procedure require. Similarly, bone function is restored using bone transport (Ilizarov method), bone graft transplant, and a combination of osteotomy and bone transport. These techniques are restricted by a variety of factors: complication rate, recovery time, and extent of damage. Finally, a more small-scale approach has been autologous chondrocyte implantation, which has shown very high success rate, has not been evaluated comparatively yet.
Engineering bone and cartilage requires several central considerations: use of suitable cell types, use of suitable scaffold, and the engineering process itself. Two cell types have been targeted for use for cartilage and bone tissue engineering: mature chondrocytes and mesenchymal stem or progenitor cells; bone marrow stromal cells are a specific type of cell that is considered an adult stem cell. The main issue with mature chondrocytes is their limited and age-dependent proliferation potential and fragile differentiation potential. This issue is bypassed when using progenitor or stem cells due to their intrinsic high proliferation and differential potentials over long period of time. Another noteworthy advantage is their ability to promote vascularization, which allows nutrients to be more easily delivered to more areas of the engineered tissue. A specific subset of these cells, bone marrow stromal cells (BMSCs), is limited by the cells’ sensitivity to their microenvironment, loss of lineage potential with doubling iterations, and their lack of telomerase. Nevertheless, it is widely use for treatment because it is easy and safe to obtain. Some of the aforementioned issues can be surmounted by addition of growth factors like fibroblast growth factor-2 (FGF-2).
Scaffolds are designed to provide physical support for the extracurricular matrix (ECM), permit diffusion of nutrients and cell waste, and integrate with the surrounding tissue. Ideally, the scaffold would degrade at a rate corresponding to the rate of production of ECM, allow vascularization, and be biocompatible and resorbable. The former has not been achieved yet. Additional major drawbacks of common scaffolds are much less-than-ideal control of cell-substrate interactions and release of active molecules such as minerals, pore size, and geometry. Currently several types of natural scaffolds are used: collagen I, fibrin, alginates, and hyaluronic acid. Synthetic scaffolds are favorable to natural ones because there is better control of substance delivery and there is less of a biohazard potential; however, this type of scaffold usually induces an immune response from the host.
More efficient, regenerative treatments of bone and cartilage lesions are being tested on animals models. Cancedda et al. makes mark of important consideration with regards to choosing an appropriate animal model for testing: the regenerative capacity, matrix layer thickness, and relative load carried by animals of different species vary greatly. Animal testing is meant to tests specific aspects of the cartilage repair ability, as opposed to how well it will work in humans; thus, a good animal model would be an adult, big animal, and its spontaneous healing would be limited by inflicting heavy damage on the tissue.
According to Cancedda et al., future work should focus on creating a matrix that is biodegradable yet resistant, permits cell filtration, survival, proliferation, differentiation, and integrates with surrounding tissue.
The encompassing scope of this article provides the reader and the scientific community with a thorough recapitulation of current bone and cartilage lesion treatment methods, with a focus on tissue engineering and the major design considerations behind this field. Moreover, critical animal model identification aspects are highlighted. This article can serve as the origin of concept generation towards better tissue engineering design by presenting what is on the table currently. It can also be used to stem more cell-control research.
I chose this article specifically because of its comprehensive scope and the crucial, prevalent clinical issue it discusses. I know that arthritis is an extremely common illness that has many sources; I was curious to know what treatments are currently on the market. These treatments can also be extrapolated to damage originating from tissue removal due to cancer, which is of great concern to me as a human being. I feel that I am much more well-informed about treatment options for such harms, when I will have to face them.
8 comments:
Have they made any progress in finding appropriate biocompatible synthetic scaffolds, or if not, do they mention any materials that they were looking into for that purpose?
Looking over the paper I see that the a lot of work was done choosing the specific types of cells to use, with embryonic stem cells being included. Do you know of any advantages to using ES cells to the progenitor cells or bone marrow cells, which would be easier to cultivate?
I noticed that there are a variety of different scaffolds, such as collagen and bioceramic materials based on hydroxyapatite. Which type of scaffold provides the best surface for proliferation and differentiation of bone cells?
To Jeff Aroyo: Bone marrow cells are quite poor stem cells. As opposed to the embryonic stem cells' immortal DNA and high differential potential, bone marrow cells lack telomerase, which preserves DNA via protection against telomere shortening, and have noteable lineage potential lost with proliferation. I would hypothesize that the main advantage of ESCs over progenitor cells is their greater differentiation potency. This trait can allow ESCs to use environmental cues to better integrate into their surroundings.
Scaffolds made of hydroxy-apatite and/or tri-calcium phosphate are of most interest to scientists in this area because they are especially integrable with bone tissue. Engineering of porous scaffolds has allowed for greater surface area for tissue regeneration and cell delivery, as well as resorbability. Mineralizing this type of scaffold brings scientists one step closer to optimizing a scaffold for cartilage regeneration.
To Matthew: Yes, indeed they have made progress in designing an appropriate scaffold for bone marrow transplant. This paper (http://www.liebertonline.com/doi/pdfplus/10.1089/ten.2006.12.1261?cookieSet=1) describes bone marrow transplant incorporating a silicon-stabilized tri-calcium phosphate porous scaffold. The experiment, in which scaffold performance was evaluated based on a multitude of parameters, demonstrated great efficacy of the improved scaffold.
Nevertheless, even more recent studies show that the silicon-stabilized tri-calcium phosphate porous scaffold is not as efficient in tissue regeneration as autologous bone deposition when incorporated with bone marrow stromal cells (http://www3.interscience.wiley.com/cgi-bin/fulltext/119755420/PDFSTART).
Would a scaffold to support cartilage regrowth necessarily have to degrade to allow vascularization, or is that only important for bone regrowth, since cartilage is avascular? Is there a reason a collagen type II scaffold hasn't been used when it is the primary component of hyaline cartilage? It seems to me that if you could place MSCs or chondrocytes in a collagen II scaffold with proteoglycans the cells would already be in the correct environment.
This idea of using a scaffold for bone regeneration is intriguing to me. I find it has great potential for aiding diseases like osteoarthritis, which my mother actually has. However, it is unfortunate that this paper mentions that the scaffold used gives off an immune response. What are ways to prevent this? Also, is it promising in today's tissue engineering technology with scaffolds that drug delivery can be efficiently immobilized on the scaffold and delivered after implanted at the lesion site?
To Audrey: There is an interesting paradox that known synthetic scaffold integrate better with the environment but they induce immune response. On the other hand, scaffolds made of natural material tend to be biohazardous. The challenging solution is to find a material that is biocompatible.
I found this interesting article about a group in Korea that designed a scaffold that can be seeded with drugs that can be held on the scaffold for "a long time" after deposition. They also use tri-calcium phosphate porous scaffold, which is nowadays the standard for cartilage tissue engineering. Here is the link: http://spie.org/x13535.xml?ArticleID=x13535.
To Chris: The rate of degradation of the scaffold should ideally be equal to the rate of ECM production by the cells. If the degradation rate is higher, then when the scaffold is completely disintegrated, the tissue volume will not be filled completely and appropriately. If the degradation rate is lower, then there will be a build up of ECM/scaffold in the microspace which has the potential of altering the biological stress distribution in the area. The former is favorable over the latter.
There is research done on collagen scaffolds. This paper actually describes collagen and collagen-hydroxyapatite scaffolds with artificial vascular system: http://www.mrs.org/s_mrs/bin.asp?CID=2587&DID=59483&DOC=FILE.PDF. Here is another paper about collagen II-glycosaminoglycan scaffold that seem to be promising for chondrogenesis. Also, this experiment (http://www.liebertonline.com/doi/abs/10.1089/ten.2006.12.459) was done using adult mesenchymcal stem cells, which makes the design more complicated because of the need for directed differentiation.
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