Professor of Polymer Science & Engineering
A “failed experiment” became a life-saving discovery by MIT Professor Ioannis V. Yannas and his colleague Dr. John Burke when their search for a better way to treat severe burn victims led to the discovery of organ regeneration.
Alum Dennis Orgill SM ’80, PhD ’83 applies the mechanical engineering principles he learned from Professor Ioannis V. Yannas to the operating room.
Yannas’ invention of artificial skin did more than just block infection and retain moisture — it actually helped to regenerate the skin.
MASSACHUSETTS INSTITUTE OF TECHNOLOGY (MIT)M.S.
The principal research interest of Dr Yannas is the process of induced organ regeneration used to replace organs that are either severely injured or are terminally diseased.
Initial discovery of dermis regeneration. In 1976 Yannas and John F. Burke, MD discovered the first scaffold with regenerative activity. Although the strctural features of a scaffold with regenerative activity were not appreciated at that time, they were eventually (1989, 2015; see references below) recognized as those of a highly porous analog of the extracellular matrix based on type I collagen, a biodegradable scaffold with highly specific structural features. These required features included a specific range of the pore size, defined degradation half-life and specified surface chemistry. When this cell-free scaffold was grafted on deep skin wounds in guinea pigs it was unexpectedly observed in 1976 that it led to strong delay of wound contraction and eventually to wound closure by formation of scarless tissue that had the appearance of dermis. The full significance of this discovery was not understood at that time; it was explained adequately about 40 years later (see below). Use of this scaffold, named dermis regeneration template (DRT), with full-thickness skin wounds in animal and humans led to synthesis of a nearly physiological dermis (1975-81). When this scaffold was seeded with keratinocytes it led to simultaneous regeneration of the dermis and the epidermis in animals and in humans (Orgill PhD thesis, 1981-83). [Early versions of the active scaffold were based on a graft copolymer of type I collagen and chondroitin 6-sulfate, a glycosaminoglycan.]
This outcome was totally unexpected: Although the epidermis regenerates spontaneously on a pre-existing dermal substrate, the completely excised dermis does not regenerate spontaneously in the adult mammal. The work eventually led to development of a medical device (commercial name: IntegraTM) that is currently used with increasing frequency to treat patients who have lost skin due to trauma, or are undergoing plastic surgery, or with patients suffering from chronic skin wounds. Its use in skin regeneration has been documented in over 300 clinical studies over the past several years, many of which are cited in the following website: http://www.ncbi.nlm.nih.gov/pubmed/?term=Integra+substitute+skin. The collagen scaffold work by the MIT group during the period 1976-1990 has provided the original paradigm in the fields of regenerative medicine and tissue engineering. This work resulted in the first patent on induced organ regeneration. (Yannas, I.V., J.F. Burke, D.P. Orgill, and E.M. Skrabut, Method of Promoting the Regeneration of Tissue at a Wound, U.S. Pat. 4,418,691, December 6, 1983).
From skin to peripheral nerves. The work with skin has been extended by Yannas and coworkers at MIT to regenerate peripheral nerves. Early work showed that the transected rat sciatic nerve was regenerated over unprecedented distances using, at first, silicone tubes filled with DRT and later simply a tubular connector based on DRT. These findings were used in an industrial laboratory to develop a commercial device (NeuragenTM) which is currently used to treat humans with paralysis of extremities resulting from severe injury (Orgill, MD thesis, 1985; L. Chamberlain PhD thesis, 1998-2000; E. Soller, PhD thesis, 2010-12). It was also used to regenerate the conjunctiva in adult rabbits (Hsu et al., 2000).
Study of the wound healing process in skin and peripheral nerves by the Yannas group showed that both organs healed by contraction and scar formation. In healing wounds, contraction is mediated by myofibroblasts (MFB), which appear to apply a planar mechanical stress field in full-thickness skin wounds and a circumferential mechanical compression field around the stump of a transected nerve. These mechanical fields have accounted well for the observed orientation of MFB axes in healing wounds in the two organs as well as the eventual orientation of collagen fibers both in dermal scar (planar orientation) and neural scar (circumferential orientation). The difference between the spatial features of wound contraction in the two organs appears to be entirely a result of differences in the macroscopic geometry of the respective organ, not due to differences in the cell biology of wound healing in each organ. This conclusion suggests the possibility that other organs which share the same wound healing process as skin and peripheral nerves may be successfully subjected to the same regenerative treatment based on use of DRT. It was eventually realized by the MIT group (2014-2016) that the entire regenerative treatment in these two organs amounted to a simple modification of the normal wound healing process. It was concluded that what was preventing the normal wound healing process from inducing regeneration (rather than normal healing by wound contraction and scar formation) was a scaffold with the appropriate surface chemistry, which would induce appropriate surface biological processes leading to blocking of wound contraction. Normal wound contraction had, therefore, to be blocked in order to induce regeneration; there was no apparent need to apply exogenous cells or active soluble substances, such as stem cells or growth factors. This conclusion simplifies greatly the methodology of organ regeneration.
Mechanism of regeneration. The molecular-biological mechanism of scaffold regenerative activity was elucidated by the same MIT group (Yannas, Tzeranis, So, 2007-2014). The regenerative activity of the DRT scaffold appears to be related closely to the known contraction blocking property of DRT. Blocking of wound contraction occurs only when the structure of the collagen scaffold has been modified to provide critical levels of the average pore diameter (20-120 µm), degradation half-life (14 ± 7 days) and required features for a specific surface chemistry. Critical features of the surface chemistry include a minimal level of ligand density for two integrins, α1β1 or α2β1, that exceeds approximately 200 μΜ α1β1 or α2β1 μΜ ligands (Tzeranis, PhD thesis, 2013-2015). Binding of a sufficient number of MFB to the ligands GFOGER and GLOGEN on the scaffold surface, during a critical period after the wound is generated, appears to explain the drastic modification of the MFB phenotype which is observed when DRT is grafted in the wound. The MFB phenotype changes due to DRT are observed as simultaneous reduction in MFB density in the wound, dispersion of MFB assemblies and disorientation of MFB long axes. This profound phenotype modification of contractile fibroblasts in the presence of DRT appears to explain the cancellation of macroscopic contraction force, an event which ushers in regeneration.
Severely injured vs diseased organs. It has been shown in numerous clinical studies that diseased skin, beset with pathology unrelated to trauma, can be regenerated provided that the diseased region of the organ has been reduced to a viable wound prior to grafting with DRT. In this clinical approach, deliberate surgical injury is inflicted in order to initiate the wound healing process, which is then modified using DRT in order to induce regeneration. For example, with skin that had become diseased by skin necrosis due to purpura fulminans (Besner and Klamar, 1998), use of DRT following skin excision led to dermis regeneration. These independent findings suggest that an organ which has become severely dysfunctional can be replaced by deliberating generating a wound in the organ, followed by grafting with DRT to induce regeenration of a functional tissue mass.
The methodology for organ regeneration described by the Yannas group appears to be applicable to organs other than skin and peripheral nerves or the conjunctiva. The necessary conditions for inducing regeenration appear to be availability of a severe, though normal, wound and treatment of that wound by a scaffold with regenerative activity. Applicability to other organs appears to require that a wound in the candidate organ heals by the same mechanism as in skin, peripheral nerves and the conjunctiva. The induced regeneration approach using an active scaffold is increasingly used as an alternative to currently popular clinical treatment of skin loss by autografting, suggesting that it may also be a viable alternative to transplantation of other organs requiring replacement. However, this method is probably not directly applicable to wounds in organs, e.g., bone, where wounds heal by processes not directly related to those in organs that have been shown capable of induced regeenration.
Description of organ regeneration methods in a monograph. Detailed references to the anatomical structures involved in regeneration and to the mechanism of regenerative activity are described in Yannas’ book Tissue and Organ Regeneration in Adults, now in its second edition (NY: Springer, 2015).
The story of a severely burned patient who was treated with IntegraTM was authored by Michael McCarthy in the book, The Sun Farmer (Chicago: Ivan R. Dee, 2007).
A 10-minute MIT video describing the clinical application of induced skin regeneration can be viewed here: A Lifesaving Discovery at MIT. In the early 1980s, before confirmation became available that the collagen scaffold induces regeneration of skin, the scaffold was commonly referred to as "artificial skin".
Honors for discoveries. For his discoveries in organ regeneration Yannas was elected to the US National Academy of Medicine (1987) and the National Academy of Engineering (2017), and was inducted in the US National Inventors Hall of Fame (2015). Other awards were also received.
Biographical information. Ioannis Yannas was born in Athens, Greece.
In 1953 Ioannis entered Harvard College and majored in Chemistry, graduating in 1957 with the A.B. degree. He then entered MIT where he earned a M.S. degree in Chemical Engineering Practice in 1959. After a period of industrial research on polymers at Grace Co., Cambridge, MA, he entered Princeton University where he earned the M.A. degree (1965) and the Ph.D degree (1966), both in Physical Chemistry. His doctoral thesis dealt with the viscoelastic behavior and thermal transitions in gelatin, the amorphous counterpart of the protein, collagen.
Since 1966 Yannas has been employed as a faculty member by Massachusetts Institute of Technology (MIT), Cambridge, MA. He currently holds a full-time appointment in the Mechanical Engineering Department. He also holds an appointment at the Harvard-MIT Health Sciences and Technology Program. He teaches classes in Biomaterials-Tissue Interactions; Tissue Engineering and Organ Regeneration; and Design of Medical Devices and Implants.
Early reports of regeneration of the dermis using the dermis regeneration template (DRT) by the MIT group in collaboration with J.F. Burke, MD, Harvard Medical School, appeared in the following:
Confirmation of regeneration of the dermis following treatment of full-thickness (dermis-free) skin wounds in adult guinea pigs was first reported in the following publications based on studies by Dr George F. Murphy, Laboratory of Dermatopathology, Brigham and Womens Hospital, Boston, MA:
Independent confirmation of regeneration of dermis was obtained by C.C. Compton, Department of Dermatology, Brigham and Women’s Hospital, Boston, MA.
Structural identification and required structural features of the dermis regeneration template (DRT) were reported in:
Early studies of peripheral nerve regeneration:
Advanced studies in peripheral nerve regeneration.
Mechanistic studies of organ regeneration
Can be supplied upon request.
Teaching Appointments at MIT
Sole author or editor
B. Papers in Refereed Journals
C. Proceedings of Refereed Conferences:
D. Other Major Publications (mostly chapters in books during 1971-2004; after 2004, chapters in books are listed under “Publications” above):
Invited Lectures: Available upon request
Theses Supervised by IV Yannas:
Patents and Patent Applications Pending: