Research Focus

Further information on Prof. Yannas' research can be found in his book, "Tissue and Organ Regeneration in Adults"

Discovery of induced regeneration of organs in adults. Synthesis of the first biologically active scaffold.

In the 1970s it was discovered in this lab that the dermis, the inner tissue layer of skin, could be regenerated (synthesized in vivo) in adult animals and later in humans. Regeneration was induced using a highly porous scaffold synthesized as a graft copolymer of type I collagen and chondroitin 6-sulfate, a glycosaminoglycan.

The discovery of dermis regeneration marked the first time that an adult tissue that does not regenerate spontaneously could be induced to regenerate. Although the mammalian fetus generally can regenerate injured organs spontaneously, adults mammals do not. When this scaffold was seeded with an appropriate density of epidermal cells from the patient (extracted from a very small biopsy of the epidermis), regeneration both of a dermis and an epidermis occurred simultaneously in about 18 days over very large areas of the body. An almost perfect new skin (skin appendages were missing) could therefore be synthesized in vivo at will without using skin grafts from the patient or from other donors. This discovery initially became known as "artificial skin".

This development of the middle 1970s and early 1980s is believed to be the first time that a scaffold, a highly porous macromolecular network optionally seeded with cells, induced synthesis of an organ, and marks the earliest years of the field that eventually, in the middle to late 1980s, became known as Tissue Engineering.

The structural requirements of scaffolds with biological activity.

The scaffold that induced dermis regeneration (dermis regeneraion template) provided its dramatic biological activity simply by being in close contact with a fresh wound at the desired anatomical site. How can a solid-like matrix possess such dramatic activity, not matched by solutions of cytokines or by cell suspensions? Scaffolds were shown to retain their activity provided that their structure incorporated certain features. The biological activity was rapidly lost when the structure deviated from these requirements.

Scaffolds were observed to have biological activity provided that 1) the identity of cell-binding ligands on their porous surface was appropriate for binding contractile fibroblasts, 2) the ligand density was sufficient to bind almost all contractile cells, 3) the structure of collagen had been modified to block platelet adhesion and aggregation, and 4) the scaffold lost its solid-like structure, degrading to soluble oligopeptides and oligosaccharides, within a period that was roughly equal to the period required for synthesis of new tissue at the anatomical site where the scaffold had been applied.

Some of these structural characteristics were also required in a scaffold (nerve regeneration template) that induced regeneration of peripheral nerves across unprecedented distances.

The theoretical mechanism of induced skin regeneration. The available data have been analyzed in great detail and the theoretical mechanism of skin regeneration, induced by the scaffold described above, has been described in detail in the volume Tissue and Organ Regeneration in Adults, New York: Springer, 2001 by I. V. Yannas.
It has been shown that a necessary (but not sufficient) condition for inducing regeneration in an injured anatomical site is inhibition of the spontaneous processes by which an injured site heals in adults. When injured, almost all organs in adults heal by closure of the injured site, using the processes of contraction and scar formation. Closure is driven mainly by contraction while scar formation is a secondary process, driven by contraction. According to the theory and as also observed in several experimental situations, active scaffolds (templates) differ from inactive ones by their ability to severely block contraction.

Application of the theory of regeneration to peripheral nerves, the conjunctiva and the kidney.

lthough the theory was developed based on extensive data from skin wounds, it was used to induce regeneration of peripheral nerves in rats and humans and of the conjunctiva in rabbits. Severe injuries in these organs close primarily by contraction and contractile cells have been observed in injured peripheral nerves and the injured conjunctiva. Studies are currently underway to find out if kidney tissue can be induced to regenerate using the same theory.

FDA-approved devices based on biologically active scaffolds.

he Food and Drug Administration (FDA) has approved use of two of these scaffolds for the treatment of loss of skin (Integra) and peripheral nerves (Neuragen, a precursor of the scaffold synthesized in this lab). Integra, the first product of the new field of Tissue Engineering, was approved in 1996 and is currently used around the world to treat skin loss in massively burned patients (thousands treated so far). It has recently being approved by the FDA to treat patients undergoing plastic and reconstructive surgery of the skin. Neuragen, approved in 2001, has so far been used with over 1000 patients with paralysis in the US.

Selected peer-reviewed publications (after 1998)

1. Yannas, I. V. (1998). Studies on the biological activity of the dermal regeneration template. Wound Rep. Reg. 6:518-524.

2. Orgill, D. P. and Yannas, I. V. (1998). Design of an artificial skin. IV. Use of island graft to isolate organ regeneration from scar synthesis and other processes leading to skin wound closure. J. Biomed. Mater. Res. 36:531-535.

3. Compton, C. C., C. E. Butler, I. V. Yannas, G. Warland and D. P. Orgill (1998). Organized skin structure is regenerated in vivo from collagen-GAG matrices seeded with autologous keratinocytes. J. Invest. Dermatol. 110:908-916.

4. Chamberlain, L. J., I. V. Yannas, H-P. Hsu, G. Strichartz and M. Spector (1998). Collagen-GAG substrate enhances the quality of nerve regeneration through collagen tubes up to level of autograft. Exp. Neurol. 154:315-329.

5. Brown, R. A., R. Prajapati, D. A. McGrouther, I. V. Yannas and M. Eastwood (1998). Tensional homeostasis in dermal fibroblasts: Mechanical responses to mechanical loading in three-dimensional substrates. J. Cell Physiol. 175:323-332.

6. Landstrom, A. and I. V. Yannas (1999). Peripheral nerve regeneration. In G. Adelman and B. H. Smith, eds. Encyclopedia of Neuroscience, 2nd ed., Elsevier, New York, pp. 1611-1613.

7. Yannas I. V. (2000). Facts and models of induced organ regeneration: Skin and peripheral nerve, In H. Garg and M. Longaker, eds. Scarless Healing. Marcel Dekker, New York, pp. 263-277.

8. Yannas, I. V. (2000). In vivo synthesis of tissues and organs. In: Lanza, R. P., R. Langer and J. Vacanti, eds., Principles of Tissue Engineering (second edition). Chapter 15, pp. 167-178. Academic Press, New York.

9. Yannas, I. V. (2000). Artificial skin and dermal equivalents. In: J. D. Bronzino, ed., The Biomedical Engineering Handbook. Chapter 138, pp.138-1 to 138-15. CRC Press, Boca Raton.

10. Yannas, I. V. (2000). Regeneration templates. In: J. D. Bronzino, ed., The Biomedical Engineering Handbook. Chapter 113, pp.113-1 to 113-18. CRC Press, Boca Raton.

11. Chamberlain, L. J., I. V. Yannas, H.-P. Hsu and M. Spector (2000). Connective tissue response to tubular implants for peripheral nerve regeneration: The role of myofibroblasts. J. Comp. Neurol. 417:415-430.

12. Chamberlain, L. J., I. V. Yannas, H-P. Hsu, G. R. Strichartz and M. Spector (2000). Near-terminus axonal structure and function following rat sciatic nerve regeneration through a collagen-GAG matrix in a 10-mm gap. J.Neurosci. Res. 60:666-677.

13. Hsu, W.-C., M. H. Spilker, I. V. Yannas, and P. A. D. Rubin (2000). Inhibition of conjunctival scarring and contraction by a porous collagen-GAG implant. Invest. Ophthalmol. Vis. Sci. 41:2404-2411.

14. Schulz-Torres, D., Freyman T. M., Yannas I. V., and Spector M. (2000). Tendon cell contraction of collagen-GAG matrices in vitro: Effect of cross-linking. Biomaterials 21:1607-1619.

15. Yannas, I. V. (2000). Synthesis of organs: In vitro or in vivo? Proc. Natl. Acad. Sci. USA 97:9354-9356.

16. Freyman, T. M. , I. V. Yannas, Y-S. Pek, R. Yokoo and L. J. Gibson (2001). Micromechanics of fibroblast contraction of a collagen-GAG matrix. Exp Cell Res. 269:140-53.

17. Spilker M. H., Asano K., Yannas I. V., Spector M. (2001). Contraction of collagen-glycosaminoglycan matrices by peripheral nerve cells in vitro. Biomaterials. 22:1085-93.

18. Freyman T. M., Yannas I. V., Yokoo R., Gibson L.J. (2001). Fibroblast contraction of a collagen-GAG matrix. Biomaterials. 22:2883-91.

19. Yannas, I. V. (2001). Tissue and Organ Regeneration in Adults. New York, Springer (book).

20. Freyman, T.M., Yannas, I.V., Gibson, L. J. (2001). Cellular Materials as Porous Scaffolds for Tissue Engineering. Progr. Mater. Sci. 46:273-282.

21. Spilker M. H., Yannas, I. V., Kostyk, S. K., Norregaard, T. V., Hsu, H.-P., Spector, M. (2001). The Effects of Tubulation on Healing and Scar Formation After Trasection of the Adult Rat Spinal Cord. Restor. Neurol. Neurosci. 18:23-38.

19. Zaleskas, J. M., Kinner, B., Freyman, T. M., Yannas, I. V., Gibson, L. J., Spector, M. (2001). Growth Factor Regulation of Smooth Muscle Actin Expression and Contraction of Human Articular Chondrocytes and Meniscal Cells in a Collagen-GAG Matrix. Exp. Cell Res. 270:21-31.

20. Freyman, T. M., Yannas, I. V., Yokoo R., and Gibson L. J. (2002). Fibroblast contractile force is independent of the stiffness which resists the contraction. Exp. Cell Res. 272:153-162.

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