[Regenerative Surgery] #3. Acellular Dermal Matrix

 

Acellular dermal matrix, developed in the form of sheet, has been used for various regeneration and reconstruction purposes, such as for burn, injury and ulcer, abdominal wall reconstruction, breasts reconstruction, vocal cord paralysis surgery and interdental papilla graft. Acellular dermal matrix is also called a ‘dermal regeneration template’ since it maintains 3-dimentional structure of the dermis, playing the role as a scaffold of various cells and stem cells.



With the development of emergency medicine since the 1970s, the survival rate of patients with extensive burns has increased, leading to the development of artificial skins for such patients. The shortage of dermis was the cause of severe scar and contracture, giving rise to the necessity of regenerating important structural and physical properties of the dermis and, as a result, the development of dermal regeneration template (acellular dermal matrix). The coverage of dermal regeneration template spans from the treatment of extensive burns to improvement of burn scars, correction of contracture, and the treatments of exposed bones, tendons, joints, and acute or chronic wounds; the indication is still in the progress of expanding. In other words, acellular dermal matrix has become an important tool and element for regenerative surgery.

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The skin is roughly composed of the epidermal tissues in the body surface and the dermis below. The main roles of the epidermis are to prevent water loss inside the body and to protect the body from foreign hazardous materials, such as bacteria and ultraviolet. The outermost multiple layers of stratum corneum, cells producing pigments and blocking ultraviolet, Langerhans cells eliciting immune function, hair cells that forms the hair, and skin appendages including sweat glands are all located in the epidermis. Basal cells, located at the bottom of the epidermis, do not have any special protective function but is the mother of various types of cells that have protective function. Small wound in the skin can heal because these basal cells make new cells constantly. The dermis under the epidermis is composed of fibrotic proteins (collagen) and fibroblasts tangled in places like threads. Since capillaries can reach up to the dermis, nutrition and various growth factors are supplied to the epidermal cells by diffusion.



Stem cells are cells that have the potential to differentiate repeatedly, with the abilities to replicate themselves and to differentiate to various tissues. Stem cells are found abundantly in an embryo after a few days of fertilization. Stem cells can be obtained, therefore, from surplus embryos produced for fertility treatment or from embryos replication without fertilization. Human muscle cells or skin cells may be obtained from these stem cells under an appropriate condition. Because of the self-replicating ability, stem cells can be mass cultured and differentiated to skin cells to obtain large amount of artificial skin.



Early artificial skin studies mainly focused on attaching temporary protective film, such as silicone or dressing, or transplanting autologous skin graft, to provide a temporary protection until new skin grows. Recent studies focus on the technology of replacing human tissues, damaged by disease, injury or aging, with cultured tissue cells to minimize rejection reaction by means of tissue engineering.



An adult patient with severe skin damage generally requires 2,000-4,000 cm² of skin graft; especially those with extensive burns require bioartificial skin proliferated tens or hundreds of times from small skin tissue. Artificial skin is a material that regenerates damaged skin, and may be divided to wound dressing, artificial dermis (acellular dermal matrix), bioartificial skin (cultured skin) depending on the roles.



1) Wound Dressing

Once a wound occurs, it is important to recover the skin structure similar to the original state. A wound, if left open for a long period of time, may accompany primary complications, such as infection, and may cause pain during the treatment period and discomfort in daily life; therefore, the wound should be closed in the early phase. In the past, it was common to attempt passive treatments, such as applying disinfectant and covering with gauze until the wound is closed. Attaching a temporary protection, such as silicone or dressing, or transplanting autologous skin graft until new skin grows, have been the most common method of temporary wound protection for burns or traumas from the early days of artificial skin study until now. Wound dressing is useful for preventing water leak from inside the body, absorbing exudate (fluid that filters from the blood vessels into lesions, in the presence of inflammation), and preventing bacterial invasion from the outside and infection. Other than gels, dressings are made of porous membrane, using polyurethane membrane or chitin, or freeze-dried pig leather.



2) Artificial Dermis (Acellular Dermal Matrix)

Artificial skin is used for wounds with skin defect due to extensive burns or surgery, and is made of synthetic or natural polymers. The upper layer is made of silicone to prevent the loss of body fluid by vaporization, and the lower layer is made of collagen, to induce angiogenesis and regeneration of connective tissues, actively helping regeneration to the original skin tissues and providing an easy passage for body cells after being disintegrated and absorbed in the body. It is hard to expect natural healing process by conservative treatment when a skin defect is very wide due to deep burns or skin cancer resection. Such cases are commonly reconstructed by skin graft or flap operation; recently, various types of dermis are available for transplantation, allowing much easier and simple covering and both functionally and aesthetically superior results. Transplantation with artificially synthesized dermal tissue may prevent severe scar and scar contracture that may happen after skin restoration to some extent. Although there might be some difference between products, artificial dermis is composed of collagens, glycoproteins and elastic fibers, which are constituents of the dermis, preventing scar formation, inducing dermal synthesis, and protecting from scar contracture. Artificial dermis is highly porous and is structured for provide a high penetration power. Structural determinants of regeneration ability in each artificial dermis are chemical constituents, size and rate of stoma, and the degeneration rate of the artificial dermis. Integra (Lifesciences, Plainsboro, NJ, USA), Pelnac (Gunze, Tokyo, Japan), Terudermis (Olympus Terumo, Tokyo, Japan), and Matriderm (Skin Health, Billerbeck, Germany) are the commonly used products in Korea.

Allogenic dermis can be classified separately from artificial dermis. Allogenic dermis is an acellular dermal matrix made from human skin by removing immunoreactive epidermal and dermal cells and then glycerol-preserved or cryopreserved, with basic 3-dimensional structure preserved in the state most similar to the actual skin. Alloderm (LifeCell, Branchburg, NJ, USA), developed in the US, is currently being imported in the Korea market. Surederm (Hans Biomed, Daejeon, Korea) and CGCryoDerm (CG Bio, Seongnam, Korea), developed in Korea, is also widely used. Dermal substitutes had been commonly used for the treatment of severe burns, but are currently being used for wound dressing and implantation in various fields, including burn, reconstructive plastic surgery, abdominal wall reconstruction and breast reconstruction.



For your information, autogenous dermal graft is an aesthetically superior skin grafting method to overcome disadvantages of conventional skin grafting. This method grafts the dermal layer only and induces epithelialization from the surrounding tissues of the recipient site to minimize hypertrophic scar in the donor site and color difference in the recipient site. The melanocytes contained in the epithelium are distributed throughout the body with different density and activity per each area, affecting the skin color. Skin graft for a wound may have different color from the surrounding tissues, therefore. Such color difference may be reduced by grafting the dermal layer only and then letting the epithelium regenerate secondarily from the epithelium of the surrounding tissues. The donor site scar can be also minimized in this manner, because the donor site can be covered again by the remaining epithelium in place. However, it takes a longer time until the epithelium is regenerated if the skin defect is large.



3) Bioartificial Skin (Cultured Skin)

Bioartificial skin may be used for extensive burns, skin ulcer due to diabetes mellitus, or skin damages. For this method, collected and cultured skin cells are attached to artificial skin to form tissues. Bioartificial skin rarely causes rejection reaction and the skin size can be modified as much as needed, even for severe burns. Because it is made from biocompatible materials according to the desired structure and function by 3-dimentional skin cell culture, bioartificial skin is a living artificial skin, almost similar to the actual skin. Among the representative products is Holoderm (TEGO Science), a cultured epidermal autograft, obtained by culturing small amount of skin (1-3 cm²) collected from the patient.



As discussed earlier, artificial dermis (acellular dermal matrix) is made by removing all cellular components, except for tissue function and structure, from collected cells, combining collagen by enzyme to strengthen the structure, and sterilizing the tissue to reduce the risk of infection before being distributed. Extracellular matrix is one of the main components of the dermis and plays an important role in the process of tissue recovery. The main constituents are hyaluronic acid, proteoglycan and collagen, and artificial dermis can replace normal extracellular matrix. Artificial dermis is normally processed from human or animal but may also be made from synthetic materials. In conclusion, artificial dermis was developed for the treatment of extensive burns and has been used as one of important strategies for reducing donor site morbidity by simpler skin graft, not flap operation, to treat and recover exacerbated inflammation of a chronic wound, such as diabetic foot, or wounds with exposed ligaments or bones. The indications for artificial dermis has rapidly expanded to be used as a scaffold for implants in breast reconstruction surgeries, for shaping in plastic surgeries, or for increasing volume in reconstruction surgeries for congenital malformations, trauma or cancer.

- To be continued -

▶ Previous Artlcle : #2. Elements of Tissue Regeneration

[Regenerative Surgery] #2. Elements of Tissue Regeneration

Defective skin and soft tissue exposing bone or tendon, mostly after injury, infection or tumor surgery, is a major challenge for plastic surgeon. In order to reconstruct the defect, engraftment on the site with tissues that are similar to the injured skin and soft tissue is necessary. Flap operation is commonly available for the reconstruction; however, local flap is limited by the amount, composition and moving range of the flap, while free flap has several other drawbacks, such as the complexity of the operation, longer operation time, and greater loss of donor site. Patients with a chronic wound, such as bedsore and diabetic foot, tend to have poor general condition and tissue flow. For these patients, it is more difficult to perform a flap operation.



Recent development in biotechnology has made it possible to make the tissues to be reconstructed by isolating and culturing cells. Particularly, adipose cells are relatively easily obtainable in considerable amount while minimizing the loss of the donor site; thus, there have been efforts to isolate Adipose Derived Stromal Cells (ADSCs) and, through cell culture and differentiation, to use them for soft tissue reconstruction. The first requisite for tissue regeneration is cells. Of course, there have been reports that wound healing was accelerated and whitening effect could be achieved by using only uncultured ADSCs. However, minimum amount of cells obtained from the donor site can be proliferated ex-vivo and then attached to a 3-dimensional, cell supporting structure, to replace organ or tissue transplantations. Therefore, requisites other than cells would include the cell supporting structure, or scaffold (substrate), blood supply for engraftment after the transplantation, and proteins, such as growth factors, to help differentiation and engraftment.

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1. Cell source

A cell is the most basic component of regeneration. Regeneration medicine approaches can be categorized to 1) cell therapy where the transplanted cells induce the production of materials required for human body to enhance tissue functioning and 2) forming framed tissues or an organ by mixing cells with biomaterials. These cells are mostly allogeneic cells or autogenous cells; allogeneic cells are obtained from the host after immunosuppression or in isolation from the immune system. However, this causes various side effects irrespective of treatment, making autogenous cells without such problems more preferable. A lot of studies using autogenous cells have been performed through animal tests and clinical trials, and the results are good as well. However, the use of autogenous cells sometimes needs an invasive surgery, and cells might be hard to collect when the tissue to be reconstructed is severely injured. Already differentiated somatic cells have limited proliferative activity, making it also difficult to obtain sufficient number of cells, and there is also the possibility of transformation or loss of tissue regenerating ability in the course of proliferation. In order to overcome these limitations, studies have been conducted on methods to secure an alternative source of cells in large amount.



In this context, stem cells than can overcome such limitations of somatic cells are gaining much attention, with a lot of studies on the subject. Stem cells normally have self-renewal ability and are defined as nonspecific cells that can differentiate to various types of mature cells. Stem cells are categorized to embryonic stem cell, fetal stem cell and adult stem cell according to the time of occurrence, or to totipotent cell, pluripotent cell, multipotent cell and unipotent cell according to the differentiation ability.



Embryonic stem cells are recognized as effective for tissue regeneration because they are most potent in proliferation and differentiation abilities. However, cell cloning technology by means of nuclear transfer is required to obtain this cell, and this cell is known to induce teratoma when transplanted directly in the human body and still carries a great risk even when the cell was properly differentiated. The use of embryonic stem cells also carries ethical controversy due to the acquisition of ovum, manipulation of embryo and its artificial destruction. Due to these issues, adult stem cell has been studied a lot in recent years. Adult stem cells have relatively weaker proliferation and differentiation abilities than embryonic stem cells, but are easy to obtain without an ethical issue, and the possibility of easy clinical application makes it an attractive target in many studies. Adult stem cells are distributed around various tissues in the human body from the bone marrow to fat, blood, heart, nerve, muscle and skin, and a lot of efforts are still being made to isolate it from various other tissues. Recent studies are investigating stem cells collected from the fat, amniotic fluid and placenta. These cell groups have similar characteristics to embryonic stem cells but do not induce tumorigenesis in the body and do not stir an ethical issue.



Another cell source currently being actively researched is Induced Pluripotent Stem Cells (iPSCs). Shinya Yamanaka at Kyoto University and John Gurdon at the University of Cambridge jointly received 2012 Novel prize for Physiology or Medicine for the study of iPSCs. iPSCs refer to cells induced to have pluripotency by artificial dedifferentiation of differentiated cells without pluripotency, and is also called dedifferentated pluripotent stem cells.



First introduced in 2006, this method transfers Oct4, Sox2, c-Myc and Klf4 genes, which are the main transcription elements of the already differentiated normal cells, by reprogramming cells to overexpress these genes to make pluripotent stem cells. According to a follow-up study, iPSCs were found to have the characteristics of embryonic stem cells, and since first induced in skin fibroblast cells of mice, iPSCs were successfully induced in human somatic cells as well. iPSCs are available for individualized production and can be used for drug screening, disease studies and reconstruction of injured tissues. However, the success rate of current reprogramming is only about 1-2% and requires more time and studies to commercialize them for clinical application.

2. Biomaterials for tissue regeneration

Biomaterials are essential for application of regeneration medicine, along with cells. Biomaterials for regeneration medicine can be used alone or in combination with cells for various purposes. When used alone, biomaterials are used for generally for restoring injured areas by filling or linking defective tissues or for normalizing the function of tissues by inducing their regeneration. On the other hand, when biomaterials are used in combination with cells, the biomaterials work as a medium to deliver cells into the body. Biomaterials for transplantation are composed of ingredients than can facilitate cell adherence and proliferation and has porous structure for smooth cell migration, angiogenesis and supply of nutrition. Such biomaterials should also be helpful for cell culture and be able to control cell phenotype without cell function or gene modification. They also have to provide a supporting role of the mechanical of physical strength required for a particular tissue and should be able to disintegrate spontaneously after a certain period of time, without leaving a foreign substance in the body. The ideal biomaterials for transplantation in the body should have confirmed biological suitability and safety, should be harmonized well with the surrounding tissues once transplanted inside the body, should not induce an inflammatory response in case of synthetic material, and should interact easily with the host. A number of biomaterials have been used so far for regeneration medicine studies, and various materials are currently being synthesized or produced for individual study purposes. Biomaterials can be broadly divided in to synthetic polymers and natural polymers. Studies using absorbable synthetic polymer compounds have been actively performed recently. Synthetic polymer compounds have several merits. They are capable of being produced in various forms, easy to handle, and available for mass production at a low cost. In addition, the raw materials to make them are easy to obtain.



On the other hand, their biosynthesis and tissue affinity are lower than the natural polymers. Along with the use of absorbable polymer compounds, studies on treating in-vivo tissues or organs to eliminate cells and components of the tissue without structural damage has been actively performed to use it as a supporting structure. A supporting structure from natural tissue has similar property to the in-vivo tissues, high affinity to cells and tissues, and contains factors that are helpful for regeneration, which is why it is used for various experiments and clinical studies.



Recent studies on biomaterials are more focused on developing an intelligent supporting structure that plays a more proactive role. Previous studies expected the supporting structure simply to deliver cells and to form a 3-dimentional structure when used in combination with cells. Recently, however, efforts have been made to give the biomaterial and supporting structure the ability to facilitate regeneration through a highly-advanced manipulation.



Such an additional function may be set differently for various purposes of a study, and can induce the production of regulators, which stimulate differentiation and proliferation of cells. Furthermore, there are also studies focused on transplanting a functional supporting structure alone in the body to activate autogenous stem cells of the host and to facilitate tissue regeneration by inducing the activated autogenous stem cells to move into the transplanted supporting structure. Another possibility has been suggested that proper manipulation of the supporting structure alone can procure and differentiate cells necessary for tissue regeneration. Such a method would be able to exclude cumbersome tissue collection, ex-vivo culture and proliferation of cells in the process of tissue regeneration and may reduce sources and time required for cell culture.



3. Vascularization of regenerated tissues

Transplanted cells and supporting structure in the body can survive by receiving nutrition and oxygen from blood vessels; therefore, rapid vascularization is essential. In order for cells to survive for a long period of time in a sizable supporting structure produced as a 3-dimentional form, oxygen and nutrition should be able to be delivered everywhere throughout the supporting structure by sufficient vascularization. To achieve this purpose, studies often use angiogenesis factor, such as Vascular Endothelial Growth Factor (VEGF). Such factors are known to stimulate neovascularization, and recent studies reported that these factors can form relatively large tissues by synergistic effect when combined with endothelial cells. Another approach is to insert genes that can produce angiogenesis factors for the same consequence, although this method may not be easy for clinical application. However, various combinations of such methods are continuously attempted. Another method to induce neovascularization is to optimize the synthesis of biomaterials and the microstructure of the supporting structure. A supporting structure with pores of proper size helps the provision of nutrition and oxygen, thereby facilitating neovascularization and infiltration.



Recently, a lot of studies are investigating the technology to make a supporting structure with microvascular networks for endothelial cells to grow on and methods to use organs or blood vessels as a supporting structure. However, such methods are still limited for forming large tissues required for actual clinical application, because biological methods using angiogenesis factors may temporarily stimulate angiogenesis but cannot maintain the effect continuously. To overcome such limitations, recently there have been efforts to prolong the lifetime of cells contained in the supporting structure, with the purpose of providing elements required for cell survival continuously until angiogenesis occurs.



One example is to insert a particulate that generates oxygen inside the supporting structure or biomaterial, where it can release oxygen continuously to maintain cell survival. Development and application of various advanced technologies are expected to accelerate the research processes of regeneration medicine and its clinical application.



4. Enhanced function of cells and supporting structures

The objective of regeneration medicine is to restore injured tissues rapidly. Therefore, more attempts are focused on transplanting tissues that have almost fully matured structure and function for more rapid recovery of the injured tissue, rather than transplanting cells or tissues with the expectation of functional recovery during the follow-up. For example, treatments using regulating factors, which mediate cell to cell interactions, and growth factors are under development. Development of new technologies, such as nanotechnology, enables genetic modification to release certain factors continuously or recently more effective delivery system of growth factors.



Among the methods to mature tissue function outside the body as best as possible is bioreactor. Biomechanical factors are known to have great influence on growth, maintenance, regression and recovery of tissues. In the process of producing tissues ex-vivo, such biomechanical stimulations similar to those inside the body are essential for successfultransplantation of the tissues into the body.



Such a bioreactor typically modifies the temperature, pH, oxygen, carbon dioxide, various nutrition, metabolites, and other regulators as required for tissue or cell culture. Recently developed high-end bioreactors can automate such a regulating function, with monitoring ability, and provides more varied biomechanical environments. Biomechanical stimulations are more effective for tissue generation of the cardiovascular system, musculoskeletal system, skin and blood vessels, which require higher strength and durability in dynamic environment. Recent developments in computer engineering and the production technique of biomaterials made more detailed simulation of biomechanical environments available. This data is used for making more functional, biomimetic artificial tissues and organs through the production of a more ideal bioreactor of the environment wanted for each tissue.



The next article will look into the acellular dermal matrix, which plays a role as a template for regeneration.



References

❶ Regenerative Surgery 3rd ed. Yu Ji and Lee Il Woo. Koonja Publishing. June 10, 2010.

❷ Neligan PC, Plastic Surgery, 3rd ed, Elsevier2013,

❸ Clinical Application of Adipose DerivedStromal Cell Autograft for Wound CoverageSeo DL, Han S, Chun KW, Kim WK J KoreanSoc Plast Reconstr Surg 2008 Nov 035(06):653-658.

- To be continued -

▶ Previous Artlcle : #1. Introduction of Regenerative Surgery and Regenerative Medicine

▶ Next Artlcle : #3. Acellular Dermal Matrix

[Regenerative Surgery] #1. Introduction of Regenerative Surgery and Regenerative Medicine

Recently, there is growing interest in regenerative surgery, one of the newer fields in plastic surgery. Currently, many types of regenerative surgery involving stem cell, PRP (platelet-rich plasma), and cell therapy, etc. are being performed. Laser along with other devices are also being used in clinical practice. Regenerative surgery or regenerative medicine is still a rather obscure field as it was recently developed. It also covers a wide range of applications which requires publication of more organized and coherent data. In this light, Professor Park Eunsoo of Plastic Surgery, Bucheon Soon Chun Hyuang University Hospital, who is an expert in regenerative surgery in Korea, contributes a series of articles on regenerative surgery. In this series, Professor Park will systematically discuss many different fields of regenerative surgery including stem cell, PRP, cell therapy, tissue engineering, and laser, etc.

Significance of stem cell and PRP in regenerative surgery

Recently, the Mainichi Shimbun of Japan reported “Shinjuku Clinic Hakatawon, a dermatologist clinic located in Hakata, Fukuoka, has been receiving patient referrals from a Korean bioventure since May 2012 and been injecting the stem cell the Korean company has cultured. Over 500 Korean patients are being treated at this clinic every month”.

Another Japanese newspaper controversially reported “A clinic in Fukuoka, Japan is performing stem cell surgery in Korean patients without safety verification.” Another report’s headline read ‘Cha Hospital of Korea improves cerebral palsy with a donor’s cord blood stem cell’. This procedure took place from May to October, 2010 involving 31 patients with cerebral palsy. Cha Hospital used the stored donor cord blood approved for clinical trial. Through immune compatibility test, they injected the cord blood that was compatible with the patient into the periphery veins. Follow-up of 6 months after injection of the cord blood showed improvement in normal body posture and motor activity as well as cognition. Magnetic resonance imaging (MRI) results also showed that the cell density in the areas on brain overseeing motor system and sensory nerves increased. Moreover, positron emission tomography-computed tomography (PET CT) that evaluates the cerebral glucose metabolism confirmed activation of the basal ganglia and thalamus which play an important role in motor ability and cognition.

Typing in the term ‘stem cell’ into an internet search engine retrieves related search words such as ‘stem cell cosmetics’, ‘stem cell breast enlargement’, ‘stem cell treatment of baldness’, ‘stem cell fat transplant’, and ‘stem cell diet’, etc. In addition, numerous clinics and hospitals are actively advertising on the internet cell-assisted fat transplantation, stem cell fat transplantation, stem cell breast augmentation, PRP (platelet-rich plasma) autologous cellular skin regeneration, PRP injection, PRP treatment of alopecia, and PRP facial autologous fat transplantation, etc.

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Stem cell and PRP technologies are expected to provide new solutions to difficult diseases and open up a new chapter of advanced medicine. However, physical, chemical and biological modification of stem cells including ex vivo culture and proliferation, etc. may cause genetic change and other side effects during processing and administration, which calls for safety verification. In other words, for clinical application of these procedures, efficacy and safety must be secured. Up to now, three stem cell therapy products have been approved and commercialized in Korea.

The first product is a treatment of acute myocardial infarction called Hearticellgram-AMI (PHARMICELL). Introduction of this product earned Korea the title of “the first country in the world to develop commercialized stem cell therapy’. Hearticellgram-AMI is a treatment that extracts mesenchymal stem cells (MSCs) from the patient’s bone marrow and after four-week isolation culture in the laboratory, it is formulated into an injection and administered in the heart.

The second product was Cartistem (MEDIPOST) which was used in the world’s first stem cell surgery conducted at Sun Orthpedics Clinic in Korea. Cartistem is the world’s first allogenic cord blood derived MSC treatment that was approved for treatment of knee cartilage defects in patients with degenerative osteoarthritis or osteoarthritis due to repeated trauma.

The third stem cell product was Cupistem (ANTEROGEN). Cupistem is an autologous adipose derived MSC treatment. It earned conditional approval for treatment of fistula in Crohn’s disease. This also was the first in the world for autologous adipose derived MSC treatment. It is well known that the commercialized stem cell therapy uses stem cells that can differentiate into a variety of body tissues, or undifferentiated cells. As they can differentiate into many types of tissue cells under the right conditions, they can be applied to regeneration of damaged tissues.

The stem cell or PRP procedures can be categorized as regenerative surgery. These two types of procedures may be the most well-known and widely performed of regenerative surgery. What are other areas of regenerative surgery besides stem cell and PRP procedures? Before we can answer that question, we should first understand the definition of regenerative surgery.

Definition of regenerative surgery

‘Regeneration’ will be the key word that plays an important role in the medicine of the near future. The dictionary definition of regeneration is ‘1. Revival from death. 2. A depraved or hopeless person rediscovering a correct way of life. 3. Reprocessing an old or broken object for use again’. The three tools for tissue regeneration in my field, plastic surgery, may be fat (adipose cell), adipose-derived stem cells, or PRP. However, AlloDerm, also known as regenerative tissue matrix, and many other artificial dermal substitutes have entered the market. Various products are introduced and being developed including commercialized growth factors (EGF, FGF), nucleic acid preparations including PDRN (polydeoxyribonucleotide) that are advertised as a tissue regeneration activator, and autologous fibroblast culture, etc.

The word ‘plastic’ in plastic surgery originates form the Greek word ‘plastikos’. This word has the meaning ‘to mold or give form’. Modern-day plastic surgery has its roots in this meaning. Plastic surgery is often understood from the perspective aesthetic enhancement, however, a more correct recognition of it may be that it corrects physical or structural defect or deformity for restoring normal function. Plastic surgery is a specialized surgical field that deals with this type of correction. In other words, plastic surgery is a type of surgery that corrects congenital or acquired physical deformity or defect to restore the normal function and form. Plastic surgery deals with all parts of the external body from head to toe. Moreover, plastic surgery includes cosmetic surgery and reconstructive surgery. Aesthetic surgery is also used to replace the term plastic surgery, however, this may be limited to the efforts to correct non-defective appearance for enhanced aesthetic effect.

On the other hand, reconstruction refers to correction and restoration of deformity or defects to normal. All types of congenital deformity including the cleft lip and cleft palate, facial deformation as well as burn scar and physical trauma from accidents, can be subjects of reconstruction which is part of plastic surgery. Moreover, reconstructive plastic surgery can be performed in combination with tumor removal. The most representative example of this is breast reconstruction performed after mastectomy.

Functional and aesthetic effects are considered in reconstructive surgery as well and the distinction between aesthetic plastic surgery and reconstructive surgery does not carry much meaning other than categorization of the patient undergoing surgery as having normal function or not. Based on this information, the regenerative surgery can be defined. First, in regenerative medicine, replacing, restoring or improving the function of congenital defect or accidental tissue or organ damage is carried out. Organ transplantation, reconstructive surgery, artificial organ transplantation, tissue engineering and cell therapy are among the methods of treatment available in regenerative medicine.

Therefore, regenerative surgery could be defined as use of the above methods or tools for tissue regeneration or application of techniques based on regenerative medicine for surgical treatment. The definition of regenerative surgery proposed in published literature differs slightly but the a study by Scala et al., published in 2012, defines regenerative surgery as ‘a new medical field in which stem cells are induced to migrate to the damaged tissue with the use of biological products (PRP, gel, etc.) or stem cells to encourage tissue proliferation and eventual tissue recovery’. In addition, the definition of regenerative surgery offered by ISPRES (International Society of Plastic Regenerative Surgery) at its website discusses reconstructive surgery using adipose-derived MSCs. The website also goes into three advantages of this new field.

First, regenerative surgery allows the possibility of minimally invasive autologous transplants. Adipose-derived MSCs are isolated through centrifugation and lipoaspiration or can be extracted and directly transplanted during surgery.

Second, with regenerative surgery, cell expansion is not necessary.

Third, regenerative surgery has made age no longer a barrier. Adipose-derived stem cells are abundant in elderly patients and have excellent regenerative effect.

Regenerative surgery and tissue engineering

In April 2012, Moral et al. published a paper in the field of orthopedics and sports medicine which discussed the link between science and surgery in regenerative surgery. This paper argued that a surgeon can repeat the benefits of regenerative medicine proven in laboratory in real patients in sports medicine.

In fact, the term ‘tissue engineering’ was first used by Joseph Vacanti of Harvard Medical School and Robert Langer of MIT, pioneers of the field in the late 1980s. The definition of tissue engineering is ‘the science that aims to restore, preserve or improve the function of an organ or tissue through developing and transplanting a biological tissue by combining basic concepts of bioengineering and engineering’. Therefore, the ultimate purpose of tissue engineering is to provide patients a healthy, disease-free life through clinical application of technology. Recent advances in related fields such as material engineering, drug and gene carrier studies, stem cell studies, and nanotechnology, etc. have expanded the application of tissue engineering and increased its use in the clinical setting. This has allowed it to evolve into a high-tech medicine that befits the name regenerative medicine.

In the case of organ transplantation, transplanting the donated organ to a recipient can bring optimal treatment effects, however, the number of donated organs falls far short of needed organs and an alternative treatment is urgently needed to tackle this problem. Reconstructive surgery uses a variety of materials to create an organ similar to the damaged organ for transplantation. It is mainly applied as part of plastic surgery and the function of transplanted material is limited.

Artificial organ transplantation refers to transplantation of metal or ceramic organs to replace the mechanical function of the damaged organ. Prosthetic hip joints, cardiac valves, and intraocular lens, etc. are currently the most widely used artificial organs. However, this method is limited to organs with little biological functions and deterioration of the material in the long-run may cause problems. Therefore, use of live tissues for tissue regeneration or function enhancement may solve the fundamental problems. Cell therapy is part of such endeavor. With cell therapy, cells or pluripotent stem cells are injected in the desired organ for regeneration. Some argue that this is the start of regenerative medicine. Moreover, tissue engineering combines the use of materials to supplement the limitations of the cell therapy.

In tissue engineering, cells that compose the organ or tissue or stem cells that may differentiate into such cells are placed into a three-dimensional scaffold (artificial substrate). Then an environment conducive to graft survival is provided through allowing blood flow into the transplant for regeneration of a damaged organ or tissue.

Three essential conditions for tissue regeneration are cells, scaffold (substrate), and blood flow and may also include growth factors or cytokines. According to a study by Smith et al. published in 2011, the three essential elements for tissue regeneration are cells, protein, and scaffold. Unlike artificial organ transplantation, after a period of time, the transplanted artificial substrate is dissolved and replaced by a new organ or tissue with natural cells and extracellular matrix. Therefore, the regenerated tissue grows as the body matures and may last semi-permanently going through the same aging process as the rest of the body.

Degradable scaffolds used in tissue regeneration can be categorized into porous and hydrogel types. Especially, minimally invasive procedure is possible using injectable hydrogel where large amounts of cells can be delivered through a needle.

The next article will take a closer look at the essential elements of tissue regeneration.

References

❶ Regenerative Surgery 3rd e). compiled by Ji Yu, Ilwoo Lee, Koonja Publishing, Copyright. June 10, 2010.

❷ Regenerative surgery for the definitive surgical repair of enterocutaneous fistula. Scala M, Spagnolo F, Strada P, Santi P. Plast Reconstr Surg. 2012 Feb;129 (2):391e-392e.

❸ Advancing regenerative surgery in orthopaedic sports medicine: the critical role of the surgeon. Moran CJ, Barry FP, Maher SA, Shannon FJ, Rodeo SA. Am J Sports Med. 2012 Apr;40 (4):934-44.

❹ Regenerative surgery in cranioplasty revisited: the role of adipose-derived stem cells and BMP-2 Smith DM, Cooper GM, Afifi AM, Mooney MP, Cray J, Rubin JP, Marra KG, Losee JE. Plast Reconst r Surg. 2011 Nov;128 (5):1053-60.

-To be continued-

▶ Next Artlcle : #2. Elements of Tissue Regeneration