®
EPIDERMAL GRAFTING
Product Evaluation and Expert Opinion
JULIE E TRIM1, ANDREW QUICK2
1. Bachelor of Science (BSc) Pharmacology, Doctor of philosophy (PhD) Molecular Pharmacology. Clinical Research Programme Manager Avita Medical.
2. Bachelor of Science (BS) and Master of Science (MS) degrees in Biomedical Engineering, Vice President Research and Technology Avita Medical.
Avita Medical Ltd. Unit B1, Beech House, Melbourn Science Park, Cambridge Road, Melbourn, Royston, Herts, United Kingdom, SG8 6HB.
The Use of ReCell® and Regenerative
Epithelial Suspension™ in Effective Treatment
of Skin Injuries and Defects
Abstract
Skin regeneration is the physiological process of restoration of normal skin. Regenerative Epithelial Suspension (RES™), naturally
features the epithelial elements needed to support the highly regulated cascade of healing events leading to regrowth of healthy
skin. RES is autologous and is made entirely at the point of care from a sample of the patient’s skin. The suspension consists of
disaggregated skin cells, including keratinocytes, fibroblasts, melanocytes and Langerhans cells. 1 In the disaggregated state, the
cells are freed from contact inhibition, and they behave as though at the edge of a wound, signaling and mediating the dynamic
processes of new tissue formation.
Keywords: wound healing, re-epithelialisation, suspension, skin graft, regenerative
Introduction
ReCell® Autologous Cell Harvesting Device (Figure 1) is a
class III, single use, sterile medical device, including a proprietary enzyme formulation that enables clinicians to produce
Regenerative Epithelial Suspension for treatment of a range
of skin injuries and defects including acute burn wounds,
chronic wounds, scar and dyspigmentation. ReCell is patented,
CE-marked, TGA registered in Australia and CFDA cleared in
China.
The clinical effectiveness of the Regenerative Epithelial
Suspension has been described in a number of published
studies (Table 1) and is the subject of a number of ongoing
randomised controlled trials: for burns in the United States,
for venous leg ulcers in the United Kingdom, for vitiligo in the
Netherlands, and for acute and chronic wounds in China.
History and Benefits
There are well-documented advantages, particularly from
a safety standpoint, to autologous techniques for epidermal
replacement. The use of autologous skin in grafting results
in a lower risk of negative outcomes in comparison to allogeneic transplantation. In 1951, Billingham and Medawar
noted allogeneic skin triggers a potent reaction by the host’s
immune system. 11,12,13 Multiple mechanisms contribute to the
rapid elimination of the allogeneic cells and subsequent rejection of the graft.14,15,16 Since rejection mechanisms are not triggered with autologous skin, there is no risk of graft failure
due to rejection and no requirement for immunosuppressive
therapy. In addition, the extensive processing and broad safety
testing for infectious disease associated with allogeneic treatments are not needed for autologous therapeutics.17
Cell culturing has historically played an important role in
patient care, especially as part of the management of extensive
20 _ JOURNAL OF WOUND TECHNOLOGY _ N° 27 _ JANUARY 2015
Figure 1. Avita Medical’s ReCell® Autologous Cell Harvesting Device is
a single-use, stand-alone, sterile medical device to enable the clinician
to produce Regenerative Epithelial Suspension™ from a small, thin,
split-thickness skin sample for immediate delivery onto a prepared
wound surface.
skin injuries. While typically autologous, cell culturing techniques involve considerable time and expense. Rheinwald
and Green first described serial cultivation of epithelial cells18,
a technique which has been used in the development of cultured epithelial autografts (CEAs). Cell culture is limited by
differences in incubation conditions for the different cell types;
fibroblasts and keratinocytes are difficult to co-culture.
Melanocytes, which are very sensitive to stress mechanisms,
proliferate slowly19,20 and die in cell culture resulting in depigmentation after CEA treatment. In contrast to cultured cells,
melanocytes contained in RES survive to localize to the epidermal side of the dermal-epidermal junction and evenly distribute melanin throughout the epidermis for normal pigmentation of the new skin.21 As preparation and delivery of
Product Evaluation and Expert Opinion
INDICATION
STUDY TITLE
SUMMARY
Burns
A randomized trial comparing ReCell® system of epidermal cells delivery versus classic skin grafts for the treatment of deep partial thickness burns.2
A prospective randomised clinical pilot study
to compare the effectiveness of Biobrane®
synthetic wound dressing, with or without
autologous cell suspension, to the local
standard treatment regimen in paediatric
scald injuries.3
Healing of widely meshed autografts using
freshly isolated autologous epidermal cells
and acellular Xe-Derma xenodermis.4
2-cohort RCT (n=82). Use of RES for effective healing with reduced donor area and less
postoperative pain (p=0.03) were observed vs
skin grafting.
3-cohort pilot RCT (n=13). Early intervention
with Biobrane® + RES was associated with
effective healing (without grafting), less pain
and better scar outcomes. Use within 4 days
of injury saved on nursing time, dressing,
analgesic and scar management costs.
Within-subject comparative study (n=14).
Healing of wound areas treated with RES and
XeDerma was of superior quality to
XeDerma alone, reducing the development
of early and late onset complications in the
extensive burns patient.
Chronic Wounds
Autologous skin cells: a new technique for
skin regeneration in diabetic and vascular
ulcers.5
Preliminary results with the use of a noncultured autologous cell suspension to
repair non-healing vascular leg ulcers.6
Randomized clinical trial of autologous skin
cell suspension combined with skin grafting
for chronic wounds.7
Four patients (diabetic, n=3; non-diabetic,
n=1) were treated using RES. Effective epithelialization with no signs of infection was
observed by 4, 6 or 8 months. No further clinical intervention of these ulcers was required.
Treatment of 12 ulcers (11 venous and 1 vasculitic) with RES resulted in a 55% mean
reduction of the surface area of 10 ulcers
and a complete healing of the remaining 2.
These preliminary results demonstrate RES
was effective in restarting the repair process
of non-healing ulcers and in reducing pain.
STSG + RES v STSG RCT (n=88). Combination
of RES with STSG grafting in chronic wounds
demonstrated improved healing rates over
STSG alone, together with a decrease in
wound recurrence and complications.
Scar reconstruction
Combination of Medical Needling and
ReCell® for Repigmentation of Hypopigmented Burn Scars.8
Use of a novel autologous cell-harvesting
device to promote epithelialization and
enhance appropriate pigmentation in scar
reconstruction.9
Patients with 1 year old hypopigmented
scars treated with RES (n=20). The combination of medical needling and RES resulted in
statistically significant objectively measured
repigmentation vs within-subject control
scar.
RES treatment of post-traumatic scars
(n=30) resulted in excellent or good aesthetic
and functional outcomes (80%) and normal
pigmentation (60%) of the patients.
Repigmentation
Evaluation for performance of ReCell for
repigmentation.
Treatment of vitiligo lesions by ReCell® vs
conventional
melanocyte-keratinocyte
transplantation(MKT): a pilot study.10
RES+ CO2 laser with UVA within-subject pilot
RCT (n=10) for patients with stable segmental vitiligo. Median re-pigmentation was 78%
for RES treated areas, O % for CO2 control or
no treatment areas (in press, personal communication).
Within-subject comparative study (n=5, MKT
vs RES). Comparable pigmentation was
observed between RES and MKT, but without
specialised laboratory facilities.
Table 1. A short summary of selected publications describing outcomes associated with the use of RES.
RES happens at the point of care, within a span of approximately 30 minutes, RES contains viable populations of the
skin cell phenotypes1 that have been shown to be essential
in the normal physical and chemical interplay between the
different cell types in wound healing.22,23,24
It is known that skin cells produce many signaling proteins
that act on themselves (autocrine) and on other cells around
them (paracrine) to produce more than one effect (pleiotropic)
on multiple cell types. The cells are inter-dependent and disruption in the concentration or timing of any of these factors
may result in failure to heal. In non-healing (chronic) wounds,
protein expression and responses to cell factors have become
dysfunctional.25 Further, this process is naturally resourceconstrained, as the primary source for cells and their
expressed cytokines is limited to the edge of the wound. (Figure 2)
While there has been interest in cells of the dermal-epidermal junction, both basal and suprabasal keratinocytes
play roles in wound re-epithelialization.26 In addition to representation of multiple cell phenotypes, the disaggregated
JANUARY 2015 _ N° 27 _ JOURNAL OF WOUND TECHNOLOGY _ 21
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Product Evaluation and Expert Opinion
Figure 2. In normal tissue repair and pigmentation, multiple cell types and cellular responses to inflammatory mediators, growth factors and
cytokines are required. At the edges of a wound, non-contact inhibited cells initiate signaling events that promote cell proliferation and motility to
facilitate, cytokine release, vascular repair and eventually wound closure.
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skin cells in RES are in the “free edge” state, and thereby
introduce a cascade of signals that regulate and promote the
sequence of healing.27 Injured keratinocytes rapidly release
Interleukin 1 (IL-1),28,29,30 acting as a paracrine signal to lymphocytes and fibroblasts31,32 and as an autocrine signal to
activate other keratinocytes, causing them to become proliferative and migratory.29,33,34 High Mobility Group box protein
1 (HMGB1) is also released early in the injury by damaged
keratinocytes to initiate a positive feedback autocrine loop
to maintain the inflammatory cascade and is critical for signaling skin repair mechanisms and dysfunction of this signal
results in impaired wound healing.35 Master regulator proteins
such as Heat Shock Protein 90 (HSP90), are rapidly secreted
by injured and “free edge” keratinocytes and fibroblasts and
orchestrate the cell signaling cascade of cell migration, angiogenesis and matrix re-modelling essential for skin regeneration.22,36,37,38 Use of RES introduces disaggregated epithelial
cells and the associated signaling across the surface of the
Figure 3. The cells in Regenerative Epithelial Suspension become activated in the process of separation from confluent tissue. The melanocytes,
fibroblasts and keratinocytes within RES are highly interactive and communicate normally with each other via secreted factors, their receptors,
and via cell/cell contacts to restore skin integrity and function. Application of RES overcomes the usual limitation of availability of healthy cells.
22 _ JOURNAL OF WOUND TECHNOLOGY _ N° 27 _ JANUARY 2015
Product Evaluation and Expert Opinion
wound, overcoming the usual limitations of the wound edge.
(Figure 3)
The absence of “neighbour” cells initiates the cascade of
cell signals that brings about cell migration and proliferation
to heal the wound.27 This contrasts with the contact inhibited
cells of split-thickness autografts and CEA, which are not
signaling for regeneration. Cells supplied by RES survive the
hostile wound environment and contribute to wound healing.39
In 1975, Rheinwald and Green first described disaggregated skin cells and the interdependence of the cell types by
demonstrating that keratinocytes proliferate and migrate
but require the presence and products of fibroblasts.18,40 In
1999, Singer and Clark reviewed the importance of all the
skin cell types in wound healing.27 It has been shown that
melanocytes, fibroblasts and keratinocytes are highly interactive and communicate with each other via secreted factors,
their receptors and via cell/cell contacts to regulate the function and phenotype of the skin.23,24 For normal tissue regeneration and pigmentation, multiple cell types and processes
are required and cellular responses to inflammatory mediators, growth factors and cytokines must be appropriate and
precisely timed.41
Conclusion
Avita Medical’s technology can be used at the point of care
to produce Regenerative Epithelial Suspension, which is a
safe, rapid, and physiologically relevant means for restoration
of normal skin. Since RES is autologous in origin, the suspension is non-antigenic with a low risk of negative sideeffects. It is readily available with the economic benefits of
low-cost and simple logistics. While understanding of the
detailed roles of each skin cell type and their interplay during
skin regeneration continues to develop, it is apparent that
disaggregated populations of cells in suspension are activated
in the process of separation from confluent tissue. The physiologically relevant and complete nature of RES underpins its
potential for restoration of normal skin characteristics.
References
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3. Wood F, Martin L, Lewis D, Rawlins J, McWilliams T, Burrows S,
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Conflict of interest: Both authors are employed by Avita Medical.
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