Principles of skin regeneration - Biomaterials for Treating Skin Loss - page 217

porous analog of ECM with a highly specific structure that degrades in vivo at a
controlled rate. Among other characteristics, regenerated skin is mechanically
competent, fully vascularized and sensitive to touch as well as heat or cold. The
regenerated dermal-epidermal junction, with its extensive formations of rete
ridges and capillary loops, leaves no doubt that the newly synthesized tissues are
clearly not scar tissue. However, regenerated skin differs from physiological skin
in the absence of skin appendages (hair follicles, sweat glands, etc). For this
reason, the regeneration of skin accomplished to date is referred to here as partial.
Seeding of the template with keratinocytes leads to simultaneous regeneration
of a dermis and an epidermis (Yannas et al ., 1981, 1982a.b, 1984, 1989; Orgill,
1983), while omission of seeded cells leads to sequential regeneration of dermis
and epidermis. The simultaneous process leads to a clinically desirable result
within about 3 weeks but is complicated by the need to prepare the seeded template
in the clinical setting. The time required for regeneration can be shortened by
culturing keratinocytes prior to seeding inside the scaffold (Butler et al ., 1999). In
spite of these considerations, the sequential process has been used extensively in
the clinical setting. In this treatment the template induces regeneration of the
dermis and the new dermis is spontaneously epithelialized from the wound margin.
However, in clinical studies of large-area wounds with DRT, rather than wait for
re-epithelialization from the edges of the wounds (a process with increased risk of
infection of the open wound), a thin autoepidermal graft has been preferably
applied to the newly synthesized dermis (Burke et al ., 1981; Heimbach et al ., 1988;
Fang et al ., 2002).
Although seeding of DRT with autologous keratinocytes was required to
accelerate the kinetics of organ regeneration, seeding was not required to effect the
eventual outcome itself (i.e. regeneration versus repair). Neither was seeding with
fibroblasts required to affect the eventual outcome. Furthermore, studies of skin
wounds under the same experimental conditions as above showed that treatment of
the wounds with a large variety of growth factors (Greenhalgh et al ., 1990;
Puolakkainen et al ., 1995), or epidermal cell suspensions or epidermal cell sheets
(Billingham and Reynolds, 1952; Carver et al ., 1993), or with a number of
scaffolds based on synthetic polymers (Cooper et al ., 1991; Hansbrough et al .,
1993), failed to induce dermis regeneration. These and related observations (for
review see Yannas, 2001) motivate study of the mechanism by which DRT induces
stroma regeneration. The insight obtained by use of DRT (see below for mecha-
nism) further sharpens the question about alternative methodology to achieve what
is currently available by use of an active scaffold.
In spite of the lack of regenerated skin appendages, the cell-free DRT scaffold
(clinically used as Integra®) that induces partial skin regeneration has been
approved by the US Food and Drug Administration (FDA) for use with patients
who have suffered massive loss of skin. Patients treated with this device were those
suffering from massive burns (Burke et al ., 1981; Heimbach et al ., 1988; Stern et
al ., 1990; Fang et al ., 2002; Klein et al ., 2005), patients undergoing plastic or