Humans have the ability to regrow cartilage, a new study has found.
In a way similar to how salamanders and other creatures can regrow lost limbs, humans have the capacity to repair and regenerate cartilage in their joints, researchers at Duke Health discovered.
“We believe that an understanding of this ‘salamander-like’ regenerative capacity in humans, and the critically missing components of this regulatory circuit, could provide the foundation for new approaches to repair joint tissues and possibly whole human limbs,” said senior author Virginia Byers Kraus, a professor in the departments of medicine, pathology and orthopedic surgery at Duke.
The researchers learned that molecules called microRNA regulate the regeneration process. These microRNAs are more active in animals known for limb, fin or tail repair, including salamanders, zebrafish, African freshwater fish and lizards.
These microRNAs are also found in humans – an evolutionary artifact that provides the capability in humans for joint tissue repair, according to a press release by Duke Health.
“We were excited to learn that the regulators of regeneration in the salamander limb appear to also be the controllers of joint tissue repair in the human limb,” lead author Ming-Feng Hsueh said. “We call it our ‘inner salamander’ capacity.”
The researchers said microRNAs could be developed as treatments to prevent, slow, or reverse arthritis.
“We believe we could boost these regulators to fully regenerate degenerated cartilage of an arthritic joint.
If we can figure out what regulators we are missing compared with salamanders, we might even be able to add the missing components back and develop a way someday to regenerate part or all of an injured human limb,” Kraus said. “We believe this is a fundamental mechanism of repair that could be applied to many tissues, not just cartilage.”
The research team also learned the “age” of cartilage depends on where it is in the body.
“Cartilage in ankles is young, it’s middle-aged in the knee and old in the hips,” they found. This could explain why knees and hips take longer than ankles to heal, and why arthritis is more common in hips and knees.
More than 10% of Americans older than 60 experience knee pain related to osteoarthritis, the most common disease of the knee joint. In osteoarthritis, the cartilage in the knee joint gradually wears away.
The Duke Health study was published in the journal Science Advances. You can read the full study here, bit.ly/310raui.
Hyaline cartilage provides a smooth articular surface and the ability to withstand good amount of pressure.
It is alymphatic, aneural, avascular loadbearing tissue, composed of chondrocytes sparsely embedded within an extracellular matrix of collagens and proteoglycans.
Articular cartilage damage has inherent limited healing potential, hence it remain as a challenging problem for orthopedic surgeons.
In the immediate past, surgeons often replaced the articular surface with implants when articular lesions become full-blown osteoarthritis.
Recently there are new orthobiological techniques in cartilage lesions with commendable effectiveness to regenerate tissue homeostasis and delay the progression of osteoarthritis.
Due to hypocellularity and avascularity, articular cartilage has limited capacity for regeneration upon injury. Articular cartilage injuries are commonly caused by sports and recreational activities. When left untreated, articular cartilage lesions can lead to osteoarthritis
Current treatment modalities for articular cartilage repair help to repair the articular cartilage lesions and reduce pain in affected joints to some degree.
Since these techniques often generate inferior fibrocartilage repair and has issues of donor-site morbidity which necessitates the search for an alternative best method. Mesenchymal stem cells (MSCs), have emerged as a promising cell source for cartilage repair. Stem cells may be delivered directly by means of injection or seeded in scaffolds for implantation. Major advantages of applying mesenchymal stem cells for cartilage repair are from their easy availability, multilineage potency and proliferative capacity.
The most modern trend includes preventive interventions and therapeutic solutions that can promote the tissue regeneration and the reduction of cartilage degeneration.
Cartilage defects are classified in to two types according to the depth of the lesion in to partial (chondral) or full thickness (osteochondral).
The healing of chondral defects do not by the host blood supply, resident macrophages and MSCs originating from the bone marrow because it not penetrate the vascularised subchondral bone. Instead the repair mostly relies on the limited mitotic activities of resident chondrocytes which are rarely effective.
On the other hand, the full thickness (osteochondral) defects are lesions that penetrate the subchondral bone, and in such cases, the bone marrow provides vascularisation and MSCs to promote the better repair.3
The poor intrinsic regenerative capacity of articular cartilage demands the importance of an effective treatment method for cartilage repair to avoid this complication.
Nonsurgical treatment of cartilage lesions has demonstrated variable results. A number of surgical procedures like marrow stimulation techniques or microfracture, osteochondral autografting/allografting and cell-based therapies have been successfully used clinically.6
Current treatment modalities
Microfracture is a common procedure in which small holes are made and distributed across the entire articular cartilage lesion site, at a distance of 3–4 mm apart and down to a depth of 4 mm, thus yielding about 3–4 holes per cm 2.7, 8, 9
It is a minimally invasive arthroscopic approach, which does not require any costly instrumentation.
The microfracture is a marrow stimulation techniques which brings the marrow cells to the defect site to help in repair.10
Mosaicplasty/Osteochondral Grafting was introduced in the early 1990s.11
Here the osteochondral plugs are taken by a cylindrical cutting device from healthy cartilaginous area in the form of cylindrical shaped plugs, and then implanted into an articular cartilage defect.
The osteochondral plugs are usually taken from the non-weight bearing peripheries of both femoral condyles near the patellofemoral joint and introduced as a mosaic to fit into the cartilage defect.
Autologous Chondrocyte Implantation (ACI) is a cell-based technique to treat the full-thickness chondral defects in the knee.12
Here the cartilage tissue is first harvested from the patient by arthroscopy from a non-weight bearing area.
Then the chondrocytes are isolated and culture in the laboratory to form a monolayer culture to get the desired population of chondrocytes.
Thereafter, they are transplanted into the cartilage defect and held in place by sewing a periosteum patch over it so as to localise the chondrocytes within the defect site.13
Stem Cells for Articular Cartilage Repair and Regeneration has recently emerged as a promising option to treat articular defects and early OA stages.
There are mesenchymal stem cells and pluripotent stem cells used in these group.
Mesenchymal Stem Cells (MSCs) are the most widely used stem cell source for articular cartilage regeneration technique.
These cells are easy to expanded to large numbers and display a strong ability to differentiate to multiple lineages including chondrogenic, osteogenic and adipogenic.3
Among the MSCs, synovium-derived MSCs have been reported to have superior proliferation and differentiation capacity into chondrocytes, supporting their use in cartilage tissue engineering and regeneration.19
Human pluripotent stem cells has the great potential of self-renewal and ability of differentiation to cell lineages of all three germ layers.20
The embryonic stem cells (ESCs) (Thomson et al., 1998) and induced pluripotent stem cells (iPSCs) (Takahashi et al., 2007) are the two major sources of pluripotent stem cells. The embryonic stem cells are isolated from the inner cell mass of embryos, where as pluripotent stem cells are created from both foetal and adult somatic cells.
Pluripotent stem cells are not suitable for direct clinical application21 because of tumorigenic property, therefore, chondrogenic differentiation of pluripotent stem cells to desired purified populations of chondroprogenitors or chondrocytes has to be done prior to transplantation.
This can be achieved by culture in defined media supplemented with growth factors and coculturing with chondrocytes.22
Stem cell behaviours are regulated by multiple microenvironmental controls. As an external signal, mechanical stiffness of the extracellular matrix is capable of governing stem cell fate determination.
In order to deliver stem cells for articular cartilage regeneration, an appropriate scaffold is important.
Biomaterials that possess the characteristics such as biocompatibility (to support the viability, expansion and differentiation of seeded cells), biodegradability (to facilitate tissue remodelling with neotissue formation and matrix deposition) and three-dimensional (3-D) structure are preferred for the scaffold.Two materials have been used as scaffolds for cartilage tissue engineering.
Polylactic acid (PLA), poly(lactic/glycolic acid) (PLGA) and polyglycolic acid (PGA) are the synthetic polymers that have also been used commonly.
Bioactive factors are another promising factors used in articular cartilage regeneration are transforming growth factor-βs (TGF-βs), insulin-like growth factor-I (IGF-I), fi broblast growth factor (FGF) and bone morphogenetic proteins (BMPs). Among BMPs, BMP-2 stimulates the proteoglycan synthesis and improve the repair of osteochondral defects,25 Similarly the combination of TGF-βs and BMPs has also been demonstrated to be effective in enhancing MSC chondrogenesis.
Oxygen Tension is the next external factor influencing the Stem cell behaviours. The ideal physiological environment of articular cartilage is in low oxygen.
It has been shown that hypoxic culture condition (5% O 2), enhances the matrix synthesis of chondrocytes with the expression of type II collagen, but declined when O 2 levels fell below 1%.26
Oxygen tension also modulate stem cell chondrogenesis and exhibits significant effects on the metabolism of articular cartilage, including changes in synthesis of glycosaminoglycans (GAGs) and secretion of growth factors by chondrocytes.26
Mechanical Forces like motion and appropriate loading of synovial joints are necessary for the proper structure, function and metabolism of the articular hyaline cartilage. Numerous reports have linked that the mechanical stress is an important modulator of the native articular cartilage metabolic activities and to serves to maintain the cartilage homeostasis.27 Where as excessive mechanical forces may lead to cartilage damage and development of osteoarthritis as well.27
Articular cartilage repair and regeneration continue to be challenging because of the poor regenerative property. Various cartilage modalities have described with great potential for improving articular cartilage therapy.
More recently, a variety of promising cell sources, biocompatible tissue engineered scaffolds, scaffoldless techniques, growth factors, and mechanical stimuli used in current articular cartilage tissue engineering have also evolved.
The role of tissue engineering in articular cartilage repair and regeneration is promising. In the pre-autologous chondrocyte transplantation Era, the British anatomist Hunter states “Cartilage injury is a troublesome thing and once injured is seldom repaired” was the general axiom for thinking about cartilage repair.
Studies have shown that microfracture techniques do not fill in the chondral defect fully, and it forms fibro cartilage rather than hyaline cartilage. The microfracture techniques became controversial due to a lack of favourable reports on the long-term effects.
In mosaicplasty the defects can be filled immediately with mature, hyaline articular cartilage is the main advantage, moreover both chondral and osteochondral defects can be treated in the same way. This procedure can be performed either as an open or arthroscopically assisted procedure
The clinical outcomes of ACI therapy are truly encouraging. It has signifi cantly reduced pain and more interestingly the formation of a hyaline-like cartilage being observed.
ACI is a two-step procedure in which the new cartilage cells are grown and then implanted in the cartilage defect. ACI is most useful for younger patients who have single defects larger than 2 cm in diameter.
ACI has the advantage of using the patient’s own cells, and it does have the disadvantage of being a two-stage procedure that requires an open incision.
The ACI technique has been proven to be a promising treatment modality for treatment of cartilage lesions and which has resulted in good clinical success.28 Way back in 1980s, it is well understood that the concept of healing cartilage with predominantly hyaline tissue is a myth. Then it was hypothesized that hyaline cartilage repair could be achieved by a cell-based approach to the problem.29 This thinking helps to develop a new method for achieving the goal of hyaline cartilage repair.
The clinical application of MSCs for the treatment of articular cartilage defects and OA shows promising results.30
MSCs are a good candidate for cell therapies and their healing potential has been explored also in terms of cartilage regeneration.31
The use of MSCs in the clinical setting though can be considered safe with good clinical improvement, positive MRI and macroscopic findings, but histologic features gave more controversial. Similarly even though numerous advancements have been made, the understanding of MSCs mechanism of action as well as their potential and limitations for the clinical use remain controversial.32
Use of scaffolds coated to chemotactically enhance mesenchymal stem cell recruitment to the repair construct is an attractive option. There is a new concept emerging suggesting the need to treat the whole joint as an organ system and not just the cartilage lesion.
Journal information:Science Advances