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Using plasma-rich growth factors in orthopaedic surgery and trauma: What does the future hold?
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In modern orthopaedic surgery, we are always challenged to identify treatment options that work safely, effectively and possibly better and less invasively than the current standards. In some cases, treatment options like plasma rich in growth factors can help the body heal itself and serve as an important recovery tool in a range of orthopaedic surgery and trauma cases.
To consider these factors, it is necessary to make a special mention of the scientist who, in 1965, discovered a substance in the extracellular bone matrix which had the capacity to induce bone formation, called bone morphogenetic protein (BMP). The scientist was Marshall R. Urist, PhD, of the United States.
Another scientist who led the way in this field was H.N. Antoniades, who studied and isolated regenerative substances and who in 1981 obtained those from the platelets. He identified two types, which he called platelet-derived growth factor (PDGF) I and PDGF II. Both were constituted from two amino acid chains of different molecular weights.
The cells of all the tissues in the human body are in a process of continuous renovation. Those cells in the bone tissue are submerged in the extracellular matrix, which is a network formed from macro-molecules. It participates actively in the cellular metabolism and regulates the behavior of the cells that come in contact with it.
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In this extracellular matrix, we can find soluble factors that are proteins. These soluble proteins include the BMPs and the growth factors. They contribute by providing volume and are involved in biological tissue function. Ultimately, they direct the embryological development of the cells, tissues and organs, and play an important role in postfetal physiology.
Tissue repair vs. regeneration
Tissue repair is essentially restoration without the original architecture or function, and so the physical and mechanical properties are inferior to the original ones. A transformation happens spontaneously and results in scarring. However, tissue regeneration is the obtainment of a restored tissue with properties that are indistinguishable from the original tissue.
The objective, therefore, is not to repair but to regenerate, to reconstruct the form and restore the function.
Regenerative biology consists of identifying the cellular and molecular differences that exist between regeneration (ie, new tissue) and repair (ie, scarring).
The success in stimulating the tissue regeneration mechanisms is based on carrying out, via artificial or natural biosubstances, cell migration, proliferation and differentiation.
One requirement for regeneration is the potential for cell division, which can be classified as labile, stable or permanent.
If the permanent cells are lost, they cannot be substituted; still, they have a long life and live in protected areas such as nerve cells. Most differentiated cells are not permanent and renew themselves. The new ones are produced in two ways: simple duplication of pre-existing cells (for example, the liver), or from nondifferentiated stem cells via a process of differentiation that involves a change in the cellular phenotype.
Common threads
There are great similarities between embryogenesis and repair. In both processes, highly important elements include the precursor cells, growth factors and the BMPs, some of which belong to the superfamily TGF-β.
Growth factors, or growth differentiation factors (GDFs), are soluble, diffusible polypeptides that regulate growth, differentiation and phenotype of numerous types of cells, such as those of the musculoskeletal system. They attach themselves to specific membrane receptors on the surface of the cell to which they are acting. This happens when they are sent from one cell to another in order to transmit a specific signal: migration, differentiation, activation, etc.
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| More orthopaedic surgeons are considering the use of plasma rich in growth factors, such as those being mixed (at left) and applied as part of some orthopaedic trauma cases. Images: Cugat R | |
Multi-tasking at the cell level
Each growth factor has one or more specific activities and actions in a specific cell depending on the particular environmental circumstances. When it is released from the cell that has produced it, the growth factor must interact with the relevant receptor and the biological action is triggered. A stimulus is transmitted to the inside of the cell, amplifying the signal and it is channeled specifically. This implies a wide spectrum of enzymes with specialized functions.
Growth factors are multifunctional; for example, on one hand they stimulate proliferation of certain types of cells, which on the other hand they inhibit the proliferation of others and cause effects not related with proliferation in other types of cells. They are involved in repair and regeneration and they regulate key processes such as mitogenesis, chemiotaxis, cell differentiation and metabolism.
Types of growth factors
The growth factors’ names reflect their activity or origin. Those found in bone tissue and the tissues involved in regeneration are:
- Platelet-derived growth factor (PDGF): It is a protein produced by the platelets, macrophages and endotelial cells and stored in the platelets’ alpha granules. It is released when the platelets group together, thus starting the coagulation cascade. The connective tissue cells of this area respond by initiating a replication process.
- Vascula endotelial growth factor (VEGF): The sequence of aminoacids has a similarity of 24% to PDGF-β, but it joins different receptors and so provokes different biological effects. It is a powerful selective mitogene for endotelial cells and produces an angiogenic action in vivo.
- Transformed growth factor (TGF-β): It is a superfamily of proteins that includes morphogenetic bone proteins and others. It has three fundamental functions: it modulates the cell proliferation (it is a suppressor); it increases the synthesis of the extracellular cell matrix and inhibits its degradation; and it produces an immunosuppressor effect.
- Acidic and basic fibroblastic growth factor (AFGF and bFGF): A wide variety of cells including fibroblasts and osteoblasts synthesize them. Four different types of receptors have been identified. They have an important role in tissue regeneration: they stimulate the proliferation of most cells involved in repair, including endothelial capillaris, endothelial vessels, fibroblasts, keranocytes, chondrocytes, mioblasts, etc.
- Insulin-like growth factor types I and II (IGF-I and IGF-II): These are found in large quantities in the bone. They increase the number of osteoclastic multinucleated cells, the differentiation and Type I Collagen biosynthesis.
- Epidermal growth factor (EGF): Its structure is similar to that of the TGF-
; it joins the same receptors and its biological action is similar, though not identical. This growth factor facilitates wound repair. It also attracts the fibroblasts by chimiotaxis, and these synthesize collagen, resulting in an increase in the total collagen.
Real-life applications
Many scientists have worked to create bone substitutes and find new techniques of improving bone healing with the goal of finding a substance that fulfils all of the desired requirements.
Initial in vivo studies were reported in the fields of oral-maxillofacial surgery and in dentistry.
Research carried out on tendons has shown that the PRGF accelerates tendon cell proliferation, stimulates the synthesis of Type I collagen and has an angiogenetic action. All these effects documented in vitro and in vivo studies are oriented towards achieving a quick and safe tendon and ligament repair/regeneration process.
In conclusion, much research and many clinical applications have been carried out in the 43 years since Marshall Urist discovered the BMP-7, and a field of research and therapeutical applications seems to be opening up. However, coinciding with reflections made by Sanchez et al, it is fundamental to arrive at a consensus about the technique for obtaining PRGF and to agree on the final biological efficacy of PRGF.
Of course, we must standardize procedures and perform more well-designed clinical trials to help further evaluation of the therapeutic impact of PRG-F.
For more information:
- Ramon Cugat, MD, PhD, is an orthopaedic surgeon with Mutualidad de Futbolistas Catalanes in Barcelona and is an editor for Orthopaedics Today Europe. He can be reached at ramon.cugat@sportrauma.com