collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
scaffold that induces regeneration of
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
in mammals such as humans. The term was used in the late 1970s and early 1980s to describe a new treatment for massive
burn
A burn is an injury to skin, or other tissues, caused by heat, electricity, chemicals, friction, or ionizing radiation (such as sunburn, caused by ultraviolet radiation). Most burns are due to heat from hot fluids (called scalding), soli ...
s. It was later discovered that treatment of deep skin wounds in adult animals and humans with this scaffold induces regeneration of the
dermis
The dermis or corium is a layer of skin between the epidermis (skin), epidermis (with which it makes up the cutis (anatomy), cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from s ...
. It has been developed commercially under the name Integra and is used in massively burned patients, during plastic surgery of the skin, and in treatment of chronic skin wounds.
Alternatively, the term "artificial skin" sometimes is used to refer to skin-like tissue grown in a laboratory, although this technology is still quite a way away from being viable for use in the medical field. 'Artificial skin' can also refer to flexible
semiconductor
A semiconductor is a material with electrical conductivity between that of a conductor and an insulator. Its conductivity can be modified by adding impurities (" doping") to its crystal structure. When two regions with different doping level ...
materials that can sense touch for those with prosthetic limbs (also experimental).
Background
The skin is the largest
organ
Organ and organs may refer to:
Biology
* Organ (biology), a group of tissues organized to serve a common function
* Organ system, a collection of organs that function together to carry out specific functions within the body.
Musical instruments
...
in the
human body
The human body is the entire structure of a Human, human being. It is composed of many different types of Cell (biology), cells that together create Tissue (biology), tissues and subsequently Organ (biology), organs and then Organ system, org ...
. Skin is made up of three layers, the
epidermis
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and Subcutaneous tissue, hypodermis. The epidermal layer provides a barrier to infection from environmental pathogens and regulates the ...
, dermis and the fat layer, also called the hypodermis. The epidermis is the outer layer of skin that keeps vital fluids in and harmful bacteria out of the body. The dermis is the inner layer of skin that contains blood vessels, nerves, hair follicles, oil, and sweat glands. Severe damage to large areas of skin exposes the human organism to
dehydration
In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
and
infection
An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
s that can result in death.
Traditional ways of dealing with large losses of skin have been to use skin grafts from the patient (autografts) or from an unrelated donor or a cadaver. The former approach has the disadvantage that there may not be enough skin available, while the latter suffers from the possibility of rejection or infection. Until the late twentieth century, skin grafts were constructed from the patient's own skin. This became a problem when skin had been damaged extensively, making it impossible to treat severely injured patients with autografts only.
Regenerated skin: discovery and clinical use
A process for inducing regeneration in skin was invented by Ioannis V. Yannas (then an assistant professor in the Fibers and Polymers Division, Department of Mechanical Engineering, at
Massachusetts Institute of Technology
The Massachusetts Institute of Technology (MIT) is a Private university, private research university in Cambridge, Massachusetts, United States. Established in 1861, MIT has played a significant role in the development of many areas of moder ...
) and John F. Burke (then chief of staff at Shriners Burns Institute in Boston, Massachusetts). Their initial objective was to discover a wound cover that would protect severe skin wounds from infection by accelerating wound closure. Several kinds of grafts made of synthetic and natural polymers were prepared and tested in a guinea pig animal model. By the late 1970s it was evident that the original objective was not reached. Instead, these experimental grafts typically did not affect the speed of wound closure. In one case, however, a particular type of collagen graft led to significant delay of wound closure. Careful study of histology samples revealed that grafts that delayed wound closure induced the synthesis of new dermis de novo at the injury site, instead of forming scar, which is the normal outcome of the spontaneous wound healing response. This was the first demonstration of regeneration of a tissue (dermis) that does not regenerate by itself in the adult mammal. After the initial discovery, further research led to the composition and fabrication of grafts that were evaluated in clinical trials. These grafts were synthesized as a graft copolymer of microfibrillar type I collagen and a glycosaminoglycan, chondroitin-6-sulfate, fabricated into porous sheets by freeze-drying, and then cross-linked by dehydrothermal treatment. Control of the structural features of the collagen scaffold (average pore size, degradation rate and surface chemistry) was eventually found to be a critical prerequisite for its unusual biological activity. In 1981
Burke
Burke (; ) is a Normans in Ireland, Norman-Irish surname, deriving from the ancient Anglo-Norman and Hiberno-Norman noble dynasty, the House of Burgh. In Ireland, the descendants of William de Burgh (''circa'' 1160–1206) had the surname'' de B ...
and Yannas proved that their artificial skin worked on
patient
A patient is any recipient of health care services that are performed by Health professional, healthcare professionals. The patient is most often Disease, ill or Major trauma, injured and in need of therapy, treatment by a physician, nurse, op ...
s with 50 to 90 percent
burn
A burn is an injury to skin, or other tissues, caused by heat, electricity, chemicals, friction, or ionizing radiation (such as sunburn, caused by ultraviolet radiation). Most burns are due to heat from hot fluids (called scalding), soli ...
s, vastly improving the chances of recovery and improved quality of life. John F. Burke also claimed, in 1981, " he Artificial skinis soft and pliable, not stiff and hard, unlike other substances used to cover burned-off skin."
Several patents were granted to MIT for the creation of collagen-based grafts that can induce dermis regeneration. U.S. Patent 4,418,691 (December 6, 1983) was cited by the
National Inventors Hall of Fame
The National Inventors Hall of Fame (NIHF) is an American not-for-profit organization, founded in 1973, which recognizes individual engineers and inventors who hold a US patent of significant technology. Besides the Hall of Fame, it also operate ...
as the key patent describing the invention of a process for regenerated skin (Inductees Natl. Inventors Hall of Fame, 2015). These patents were later translated into a commercial product by
Integra LifeSciences
Integra LifeSciences Holdings Corporation is a global medical device manufacturing company headquartered in Princeton, New Jersey. Founded in 1989, the company manufactures products for skin regeneration, neurosurgery, reconstructive and general ...
Corp., a company founded in 1989. Integra Dermal Regeneration Template received FDA approval in 1996, and the FDA listed it as a "Significant Medical Device Breakthrough" in the same year. Since then, it has been applied worldwide to treat patients who are in need of new skin to treat massive burns and traumatic skin wounds, those undergoing plastic surgery of the skin, as well as others who have certain forms of skin cancer.
In clinical practice, a thin graft sheet manufactured from the active collagen scaffold is placed on the injury site, which is then covered with a thin sheet of silicone elastomer that protects the wound site from bacterial infection and dehydration. The graft can be seeded with autologous cells (keratinocytes) in order to accelerate wound closure, however the presence of these cells is not required for regenerating the dermis. Grafting skin wounds with Integra leads to the synthesis of normal vascularized and innervated dermis de novo, followed by re-epithelization and formation of epidermis. Although early versions of the scaffold were not capable of regenerating hair follicles and sweat glands, later developments by S.T Boyce and coworkers led to solution of this problem.
The mechanism of regeneration using an active collagen scaffold has been largely clarified. The scaffold retains regenerative activity provided that it has been prepared with appropriate levels of the specific surface (pore size in range 20-125 μm), degradation rate (degradation half-life 14 ± 7 days) and surface chemical features (ligand densities for integrins α1β1 and α2β1 must exceed approximately 200 μΜ α1β1 and α2β1 ligands). It has been hypothesized that specific binding of a sufficient number of contractile cells (myofibroblasts) on the scaffold surface, occurring within a narrow time window, is required for induction of skin regeneration in the presence of this scaffold. Studies with skin wounds have been extended to transected peripheral nerves, and the combined evidence supports a common regeneration mechanism for skin and peripheral nerves using this scaffold.
Design considerations
Fabricating artificial skin has the difficulty of mimicking living tissue with similar biological and mechanical performance. As outlined by Integra founders Yannas and Burke, there are three key factors to consider in the creation of artificial skin: material, bio/physiochemical properties, and
mechanical properties
A material property is an intensive property of a material, i.e., a physical property or chemical property that does not depend on the amount of the material. These quantitative properties may be used as a metric by which the benefits of one mate ...
.
Material
Material selection is the most important part for designing artificial skin. It needs to be biocompatible with the body while having adequate properties for adequate function. Human skin is made of
type I collagen
Type I collagen is the most abundant collagen of the human body, consisting of around 90% of the body's total collagen in vertebrates. Due to this, it is also the most abundant protein type found in all vertebrates. Type I forms large, eosinop ...
,
elastin
Elastin is a protein encoded by the ''ELN'' gene in humans and several other animals. Elastin is a key component in the extracellular matrix of gnathostomes (jawed vertebrates). It is highly Elasticity (physics), elastic and present in connective ...
, and
glycosaminoglycan
Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case o ...
. The artificial skin by Integra is made of a
copolymer
In polymer chemistry, a copolymer is a polymer derived from more than one species of monomer. The polymerization of monomers into copolymers is called copolymerization. Copolymers obtained from the copolymerization of two monomer species are som ...
composed of collagen and glycosaminoglycan. Collagen is a
hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are n ...
polymer whose degradation and stiffness can controlled by the degree of cross linking. However, it can be
brittle
A material is brittle if, when subjected to stress, it fractures with little elastic deformation and without significant plastic deformation. Brittle materials absorb relatively little energy prior to fracture, even those of high strength. ...
and susceptible to breakdown by the enzyme collagenase. In order to make the material tougher and more resistant, a copolymer is formed with glycosaminoglycan (GAG). GAGs are long polysaccharides that act as shock absorbers. Collagen-GAG (CG) matrices have a higher modulus of elasticity and energy needed to fracture than collagen alone, making it a more ideal material. An outer layer of
silicone
In Organosilicon chemistry, organosilicon and polymer chemistry, a silicone or polysiloxane is a polymer composed of repeating units of siloxane (, where R = Organyl group, organic group). They are typically colorless oils or elastomer, rubber ...
is normally applied to the matrix in order to serve as a protective layer. Another material that can be used in synthetic skin is elastin. Elastin has a similar effect to GAG as it reduces the tensile strength and compressive modulus of the material while increasing its
toughness
In materials science and metallurgy, toughness is the ability of a material to absorb energy and plastically deform without fracturing.
Mechanical properties
Not only does the material have to be biocompatible and conducive to proliferation, it also has to have mechanical properties similar to that of real skin in order to serve as an adequate substitute. Skin is the first line of defense for the body, so it is subject to lots of chemical and mechanical assaults. As such, the artificial skin needs to be strong and tear resistant from stretching that occurs in everyday activity. It also needs to be strong enough to resist sutures from surgery. Stiffness can be controlled in several ways. As previously mentioned, crosslinking through chemical or biophysical methods. Chemical methods produce stronger materials, but biophysical methods are more conducive to cell proliferation. Furthermore, it has been noted that skin is
viscoelastic
In materials science and continuum mechanics, viscoelasticity is the property of materials that exhibit both Viscosity, viscous and Elasticity (physics), elastic characteristics when undergoing deformation (engineering), deformation. Viscous mate ...
and undergoes
hysteresis
Hysteresis is the dependence of the state of a system on its history. For example, a magnet may have more than one possible magnetic moment in a given magnetic field, depending on how the field changed in the past. Plots of a single component of ...
- it has a time dependent stress relaxation factor and goes through a separate path during unloading.
Another important consideration is the wettability of the material. This is the ability of a liquid to maintain contact with a solid surface. If the CG matrix membrane does not wet the woundbed substrate properly, air pockets can form which will lead to infection. The membrane must not be too stiff so it can drape over the surface. Furthermore, shear (lateral) or peeling (normal) forces can displace the membrane such that air pockets can reform. This can be mitigated by adding an adhesive bond like
eschar
Eschar (; ; ; or ''an'' eschar) is a slough or piece of necrosis, dead tissue that is cast off from the surface of the skin, particularly after a Burn, burn injury, but also seen in gangrene, Ulcer (dermatology), ulcer, mycosis, fungal infection ...
or scab between the two surfaces. Although the mechanical properties of the synthetic skin do not need to be exactly the same as human, the main ones that should be similar include modulus of elasticity, tear strength, and fracture energy.
Biophysical and physiochemical properties
Ultimately, the goal of the synthetic skin is to close the wound and regrow new skin. This means it first adheres to the wound and creates an airtight seal where neodermal growth can occur. During this time, the synthetic skin must degrade such that there is space for the newly grown skin. Thus, biocompatibility and degradability are also under consideration for design.
Further research
Research is continually being done on artificial skin. Newer technologies, such as an autologousspray-on skin produced by Avita Medical, are being tested in efforts to accelerate
healing
With physical trauma or disease suffered by an organism, healing involves the repairing of damaged tissue(s), organs and the biological system as a whole and resumption of (normal) functioning. Medicine includes the process by which the cells ...
and minimize scarring.
The
Fraunhofer Institute
The Fraunhofer Society () is a German publicly-owned research organization with 76institutes spread throughout Germany, each focusing on different fields of applied science (as opposed to the Max Planck Society, which works primarily on basic sc ...
for Interfacial Engineering and Biotechnology is working towards a fully
automated
Automation describes a wide range of technologies that reduce human intervention in processes, mainly by predetermining decision criteria, subprocess relationships, and related actions, as well as embodying those predeterminations in machine ...
process for producing artificial skin. Their goal is a simple two-layer skin without blood vessels that can be used to study how skin interacts with consumer products, such as creams and medicines. They hope to eventually produce more complex skin that can be used in transplants.
Hanna Wendt, and a team of her colleagues in the Department of Plastic, Hand and Reconstructive Surgery at Medical School Hannover Germany, have found a method for creating artificial skin using
spider silk
Spider silk is a protein fibre or silk spun by spiders. Spiders use silk to make webs or other structures that function as adhesive traps to catch prey, to entangle and restrain prey before biting, to transmit tactile information, or as nest ...
. Before this, however, artificial skin was grown using materials like
collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
. These materials did not seem strong enough. Instead, Wendt and her team turned to spider silk, which is known to be 5 times stronger than
Kevlar
Kevlar (para-aramid) is a strong, heat-resistant synthetic fiber, related to other aramids such as Nomex and Technora. Developed by Stephanie Kwolek at DuPont in 1965, the high-strength material was first used commercially in the early 1970s as ...
. The silk is harvested by "milking" the silk glands of golden orb web spiders. The silk was spooled as it was harvested, and then it was woven into a rectangular steel frame. The steel frame was 0.7 mm thick, and the resulting weave was easy to handle or sterilize. Human skin cells were added to the meshwork silk and were found to flourish under an environment providing nutrients, warmth and air. However at this time, using spider silk to grow artificial skin in mass quantities is not practical because of the tedious process of harvesting spider silk.
Australian researchers are currently searching for a new, innovative way to produce artificial skin. This would produce artificial skin more quickly and in a more efficient way. The skin produced would only be 1 millimeter thick and would only be used to rebuild the epidermis. They can also make the skin 1.5 millimetres thick, which would allow the dermis to repair itself if needed. This would require
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
from a donation or from the patient's body. The bone marrow would be used as a "seed", and would be placed in the grafts to mimic the dermis. This has been tested on animals and has been proven to work with animal skin.
Professor Maitz said, "In Australia, someone with a full-thickness burn to up to 80 per cent of their body surface area has every prospect of surviving the injury... However their quality of life remains questionable as we're unable, at present, to replace the burned skin with normal skin...We're committed to ensuring the pain of survival is worth it, by developing a living skin equivalent."
Synthetic skin
Another form of "artificial skin" has been created out of flexible
semiconductor
A semiconductor is a material with electrical conductivity between that of a conductor and an insulator. Its conductivity can be modified by adding impurities (" doping") to its crystal structure. When two regions with different doping level ...
materials that can sense touch for those with prosthetic limbs. The artificial skin is anticipated to augment
robotics
Robotics is the interdisciplinary study and practice of the design, construction, operation, and use of robots.
Within mechanical engineering, robotics is the design and construction of the physical structures of robots, while in computer s ...
in conducting rudimentary jobs that would be considered delicate and require sensitive "touch". Scientists found that by applying a layer of rubber with two parallel electrodes that stored electrical charges inside of the artificial skin, tiny amounts of pressure could be detected. When pressure is exerted, the electrical charge in the rubber is changed and the change is detected by the electrodes.
However, the film is so small that when pressure is applied to the skin, the molecules have nowhere to move and become entangled. The molecules also fail to return to their original shape when the pressure is removed. A recent development in the synthetic skin technique has been made by imparting the color changing properties to the thin layer of silicon with the help of artificial ridges which reflect a very specific wavelength of light. By tuning the spaces between these ridges, color to be reflected by the skin can be controlled. This technology can be used in color-shifting camouflages and sensors that can detect otherwise imperceptible defects in buildings, bridges, and aircraft.
Hospital General Universitario Gregorio Marañón
The Hospital General Universitario Gregorio Marañón is a public general hospital located at the neighborhood of Ibiza in Madrid, Spain, part of the hospital network of the Servicio Madrileño de Salud (SERMAS).
It is one of the healthcare insti ...
and BioDan Group created a 3D bioprinter capable of creating human skin that functions exactly as real skin does.
References
{{reflist
Skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...