Skin Regeneration Symposium Cambridge, 12-13 April 2016 Part 1

The Annual Skin Regeneration Symposium, held in Cambridge, UK, 12-13 April 2016, explored the latest advancements in skin repair, regeneration and restoration, and the impact this has on patients. With over 140 delegates from the disciplines of burn and trauma care, chronic wounds and esthetic medicine, the Symposium sparked lively debate and the sharing of results from interesting case studies, clinical trials and basic research to support the use of a Regenerative Epithelial Suspension produced using the ReCell® technology. Furthermore, it enabled delegates and speakers alike to share ideas and discuss how to improve the quality of care for patients.

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May 24, 2016
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Introduction

Regenerative Epithelial Suspension (RES) features all the epithelial elements needed to support the healing cascade, leading to the restoration of normal healthy skin [1]. It is an autologous preparation produced using the ReCell®, ReNovaCell™ or ReGenerCell™ medical device at point of care using a sample of the patient’s own skin.

The innovator behind RES technology, Professor Fiona Wood (Fiona Stanley Hospital and Princess Margaret Hospital for Children, Australia), welcomed delegates to the Symposium with opening remarks on the importance of regenerative medicine, the body’s healing responses and the role of cell-based technologies in epidermal and dermal repair. Use of RES has been incorporated into routine clinical practice as an adjunct to standard care, but there are still barriers to implementation that remain to be understood, as well as how cell-based therapies can influence effective skin regeneration going forward.

Skin is highly regenerative, but when breached it can cause significant pathologies beyond that of the original site of injury and may lead to harm to the person as a whole. It is therefore time to raise the bar in treatment – beyond what is perceived as the ‘gold standard’. Research has found that the impact of a burn injury can in turn impact on the patient’s life trajectory as a whole – even if they survive [2]. Restoration of good-quality skin plays a significant role in this outcome. Scarring itself is an abnormal construct, and the impact of the altered skin structure on other body systems, including immune response, is an area of research in its infancy. However, what is known is that regeneration rather than scar formation is key; how healing can be improved to reduce this impact must be explored. Use of an autologous skin cell suspension containing all the cell types found in normal skin is an important part of regeneration. Driving the technology forward, building on previous success and sharing experiences is essential for the outcomes and quality of life (QoL) of the patients we treat.

Transforming lives: the use of ReCell® in the Taiwan Waterpark Mass Casualty event

In the opening lecture, Dr Hung-Hui Liu (Taiwan Tri-Service General Hospital) shared the successful experience of using the RES produced using the ReCell® technology in burn patients following the 27th June 2015 Formosa Water Park explosion. Of the 500 people injured, more than half had a greater than 40% total burn surface area (TBSA), and 22 a greater than 80% TBSA. The Taiwan Tri-Service General Hospital admitted 61 injured patients. Of these, 31 had greater than 40% TBSA and four a greater than 80% TBSA. All of these patients were treated successfully and survived. A crisis management protocol was implemented and a plastic surgery ward was converted into a dedicated burns center with a large multidisciplinary team. This team met every morning to discuss patient conditions and agree treatment plans.

The Tri-Service team initiated twice daily dressing changes and a modified Parkland fluid resuscitation protocol based on Dr Jeffrey Saffle’s 2009 burn protocol [3,4] monitoring cardiac index (CI) and stroke volume variation (SVV) were monitored using FloTrac®/Vigileo® (Edwards Lifesciences) to optimize outcomes. Patients with a greater than or equal to 12% SVV were placed on fluids and CI was maintained at 2.5; if less than 12% SVV, urine output was monitored. The team adjusted the intravenous rate based on each patient’s urine output. This was repeated hourly. Ten patients were placed on this protocol, with an average TBSA of 61.5%, all of whom were mechanically ventilated and sedated. Compared with the traditional Parkland formula, the team had completed fluid resuscitation within the first 32h. In the first 24h the amount of fluid was 4.1ml/kg, which decreased to 2.0ml/kg burn TBSA over the next 24h. There was no sustained shock among patients beyond 48h.

Early and aggressive interventions were key to success. All patients received escharotomy and no patients required amputation. Early debridement and skin grafting was carried out, but as all patients had severe burns, there was a limit to the number of donor sites available. However, Taiwan Tri-Service General Hospital stores cadaveric skin, and was able to make use of cell suspensions in combination with meshed skin grafts to reduce the amount of donor skin required. This was produced using ReCell® in six patients with an average burn TBSA of 65% (Table 1).

Table 1. Case examples from Taiwan Tri-Service General Hospital

Case number

Age (years)

Gender

TBSA

Area

Treatment method

1

27

M

80%

Bilateral lower leg

Trunk

Left upper arm

MEEK (1:6) + ReCell® (failed owing to sepsis infection)

Mesh (1:3) + ReCell®

Mesh (1:3) + ReCell®

2

19

F

55%

Left upper & lower limbs

Mesh (1:1.5) + ReCell®

3

22

M

55%

Right upper arm, forearm & left hand

Bilateral lower legs

Mesh (1:1.5) + ReCell® (ReCell® not used immediately, but only after poor healing noticed in right arm; after 1 week with ReCell® healing was almost complete. ReCell then used over hand and forearm - after 4 weeks excellent healing was seen. On bilateral leg healing was almost completed after 2 weeks. 4-weeks post-treatment scarring was minimal)

4

21

M

60%

Left lower leg

MEEK (1:4) + ReCell® + VAC [results shown in Figure 1]

5

26

M

80%

Trunk

Right foot

MEEK (1:4) + ReCell® + VAC

6

23

M

60%

Right upper limb

Right lower leg

MEEK (1:4) + ReCell® + VAC

F=female; M=male; TBSA=total burn surface area

Due to limitations in availability of the ReCell® device at the time, RES was applied on alternate sides. By doing so the team was able to demonstrate some very obvious differences in treatment outcome. Sites treated with RES displayed faster epithelization, particularly when combined with VAC (Figure 1). During follow-up minimal scarring and contracture of the RES treated areas were observed by clinician and patient. Overall, it proved effective for severe and moderate burn patients and the team plans to include ReCell® in combination with other treatment modalities at the Tri-Service General Hospital.

Figure 1. Left leg treated with MEEK (1:4), VAC, and RES with ReCell®, (a) before treatment, (b) at 2 weeks, (c) at 5.5 weeks, (d) at 2 months

REPAIR: BURNS AND TRAUMA

The compassionate use of ReCell® in treating major burns: a single-centre experience

Dr James H Holmes IV (Wake Forest University School of Medicine, USA) presented the keynote lecture in the Burns and Trauma section of the Symposium. His experience with ReCell® dates to 2007 when the first clinical trial started in the USA. ReCell® is currently an investigational device in the USA and under clinical evaluation in preparation for application for regulatory approval. ReCell® is also available on a limited basis, through an investigational device exemption for compassionate use. In the Compassionate Use protocol developed by Dr Holmes and colleagues, ReCell® is used to produce RES, which is sprayed over meshed split-thickness skin grafts with a minimum expansion ratio of 3:1. RES is also applied to donor sites and other areas of partial-thickness burn injury. The populations treated include: adults with a TBSA of 40% or more and pediatrics with a 30% TBSA threshold in older children, and as low as 20% in younger children with poor donor site options.

Dr Holmes described the two-step procedure used in the Compassionate Use protocol. The first step involves complete excision of the dermis back to viable tissue. A dermal substitute, such as Integra® (Integra Lifesciences Corporation) or PriMatrix® (TEI Medical Inc.), was applied as needed, or wounds were covered with a cadaveric allograft to prepare the injuries for autografting. The second procedure of epithelial autografting combined meshed split-skin autograft with RES to fill in the interstices. All donor sites were also treated with RES. Dr Holmes noted they had not experienced any significant episodes of infection or graft loss using this protocol.

To date, the team has treated a total of 16 patients using this protocol, comprising 10 adults and six children, all of whom were treated for burn wounds (case examples presented in Table 2). In the adult cohort nine patients were treated. The mean age was 64 years with an average TBSA of 63%. As a result of treatment, Holmes et al. were able to reduce mean length of stay (LOS) by approximately 50% compared with matched historical controls.

Table 2. Case examples from the compassionate use of ReCell® in the USA


Age (years)

% TBSA

LOS (days)

LOS/
%TBSA

Cm2 at excision

Cm2 at ReCell #1

Cm2 at ReCell #2

Cm2 at ReCell #3

Total ops

Case 1

19

75

98

1.31*

11,625

4750

365

None

3

Case 2

39

63

61

0.97

13,439

7789

3250

None

3

Case 3

36

64

37

0.58

5,412

12,232

None

None

2

LOS=length of stay; TBSA=total burn surface area

The children were treated with RES to minimize the large amount of donor skin required to treat their wounds. The mean age of the five remaining acute burn patients was 16 months, with an average 30% TBSA. Since the treatment of children was new at the Center they do not have matched historical controls but report reduced healing time with good scar outcomes, reduced mesh patterns and no contracture.

In summary, Dr Holmes et al. found that the wounds consistently closed within 5-8 days and as a result, LOS has been reduced.

7 years of ReCell® at the Chelsea Burns Service

The Chelsea Burns Service was one of the first centers in the UK to start using ReCell® in 2009, explained Miss Isabel Jones (Chelsea and Westminster Hospital, UK). The Service has carried out 80-90 cases to date, which are almost exclusively burn wounds.

Miss Jones presented a number of the cases who had presented to her department with mixed depth burn wounds on the face (n=15), rest of body (n=15), and pediatric patients with scalds (n=6). The patients with facial burns ranged from 10 months to 54 years old, with TBSA of up to 40%. The Chelsea Burns Service will use ReCell® to produce RES at between 1 and 23 days post-injury. In their opinion and based on clinical experience, the early use of ReCell® is appropriate, especially if they expect healing complications (scar, dyspigmentaion) on the face.

Of the 15 patients with facial burns, 12 healed within 4 weeks of the burn injury and treatment with RES with no permanent scarring. Three of the patients had deep dermal injury requiring additional reconstruction, but Miss Jones used the cell suspension as an adjunct to promote healing.

Miss Jones also presented data from 15 patients with mixed dermal burns on other areas of the body whose ages ranged from a few months to 60 years, and with 4-90% TBSA. RES produced using ReCell® was applied to the prepared wound bed between days 1 and 25 and in over half of the cases, the wounds healed without the requirement for further surgery. Miss Jones discussed the specific case of a female patient in whom, at 2 weeks post-injury, healing was not progressing well. The team decided to apply split-thickness skin graft to the back of the patient’s legs and then apply cell suspensions. One week after the procedure, the graft had taken and healing was proceeding normally.

Of particular note were the pediatric cases in which Miss Jones has used ReCell®. She presented the successful case of a 12-month-old baby who was treated with a combination of biological dressings (Biobrane®, Smith and Nephew) and ReCell® within 24h following a mixed-depth scald injury. Additional procedures were not required and by 6 months she had healed remarkably well with minimal scarring of the skin. At 18 months post-injury the site of the injury was no longer visible.

Miss Jones also remarked on the use of RES on skin graft donor sites and risk of the development of a chronic wound (failure to heal after 6 weeks) at the donor site following surgery. Miss Jones presented a number of cases of patients with burn donor sites that had failed to heal. The patients (n=23), with an age range of 13-40 years, included eight young patients who had problems healing prior to the skin graft: eight healed in less than 2 weeks, nine in 13-40 days, and there were a few outliers (one passed away, one did not heal at all, and a few took more than 49 days to heal).

Miss Jones asserted that ReCell® is a great adjunct to care, is easily combined with other treatment modalities and helped to optimize the outcomes she achieved in these patients.

ReCell® – St. Andrew’s Burn Unit experience

The St Andrew’s Centre for Plastics and Burns (Chelmsford, UK) has successfully incorporated the ReCell® device into their standard practice and Ms Natalie Whybro presented a 3-year retrospective review of burn management practice with ReCell® at the Center. The data presented included a total of 100 patients with scalds and acute flame burns (Table 3). As part of the St Andrew’s protocol RES is applied to the site of injury with meshed skin grafts and the donor site. Ms Whybro commented on the successful outcomes they have achieved, with limited scarring and complications. However, a full retrospective review was difficult due to incomplete records on many of these patients. The Team at the center continues to incorporate the ReCell® device into their burns surgery and are participating in ongoing research into the effectiveness of the device.

Table 3. Data gathered as part of St Andrew’s Burn Unit review

Demographics

Total 100 patients, age 9 months to 75 years

Caucasian 57%, African 26%, South Asian 15%, mixed race 2%

Median 17.5% TBSA

Mode of injury

Adults – acute flame burns

Children - scalds

Site of injury

facial (24), trunk (41) and upper limb (35)

Treatment modalities

ReCell® and Biobrane®

ReCell® and meshed autografts

ReCell® for donor sites

TBSA=total burn surface area

The use of ReCell® on the burned child

Dr Elvira Conti (Hospital A. Trousseau, France) specializes in the use of ReCell® in pediatric burns to the face and to children with darker colored skin. She discussed 35 cases of pediatric burn treatments combining RES into her standard of care. Her patients are mostly aged between 3 months and 15 years presenting with deep second- and third-degree burns with less than 10% TBSA (Table 4).

Table 4. Case examples on the use of ReCell® on the burned child

Case number

Age

Gender

Injury

Treatment & results

1

6 yrs

M

Deep burns, 16% TBSA

Following failure of skin graft, large mesh graft 6:1 and ReCell® was used. Reduced donor skin, good skin pliability and pigmentation achieved.

2

8 mo

F

Deep, extensive scald, 17% TBSA

Following excision and temporary cover a large mesh graft and ReCell® were applied to the buttocks. Reduced donor skin requirement and reduction in mesh pattern following healing.

3

11 mo

M

Deep burn from an over-hot bath

Extrusion plus infrared lamp for 10-15 days, large mesh graft and suspension using ReCell®. After 4 months a good flexibility of the skin had returned.

4

7 yrs

M

Burn with hot metal

High risk patient (hemophilia), large donor sites contra-indicated. Treatment was RES alone with a small donor site (also treated with RES) and healed by 10 days.

5

9 mo

F

Scalp burn

Treated with RES alone to reduce donor skin burden. After 9 months news skin with limited scarring and good pliability.

6

12 yrs

M

Scald burn to the arm

After 7 weeks failure to heal in dressings alone. RES applied under local anesthesia and complete healing achieved by 20 days.

F=female; M=male; RES=Regenerative Epithelial Suspension; TBSA=total burn surface area

Long-term outcomes of ReCell® in pediatric partial thickness scalds

It is estimated that there are 250,000 burn injuries annually in UK [5], one third of which occur in children, with scalds attributable to 65% of these injuries [5, 6]. The aim of the retrospective study of 100 consecutive partial-thickness pediatric scalds by the Pinderfields team and presented by Dr Elliott Cochrane (Yorkshire and Humber Deanery, UK) was to examine the incidence of scar complications (e.g., keloid and hypertrophic scarring, itching, dyspigmentation) following a number of different treatments and combinations.

The average size of burns seen was 5%, usually affecting the upper limbs or chest, and of varying depth. Five treatment modalities were used and included standard dressings, biological dressings (Biobrane®), split-thickness skin grafts, ReCell® and Biobrane® plus ReCell®: 39 patients had dressings only; 22 were treated with Biobrane®; 26 had split-thickness skin grafting; nine patients had a combination of Biobrane® and ReCell®; four patients received ReCell® alone.

Dr Cochrane discussed the impact of severity and depth of the burn on the treatment modality used. Of note was the success the team has achieved with the use of biological dressings on partial thickness scalds. The team achieved healing, avoiding further surgical intervention when children were treated with Biobrane®; however, over 50% reported scarring and dyspigmentation. When biological dressings were applied over RES, this drops to only 25% of patients reporting scarring and dyspigmentation. In addition, a reduction in itch was also noted.

These data sets are currently undergoing statistical analysis pending publication and ReCell® remains part of the pediatric burns protocol at Pinderfields Hospital.

ReCell® utilization with skin substitutes and broadening therapeutic options

Miss Alex Murray (Stoke Mandeville Hospital, UK) presented her team’s approach to using dermal substitutes in combination with RES produced by the ReCell® device in major burns and complex soft tissue loss, and how therapeutic options can be broadened in these techniques.

In major burns initial wound scrub, escharotomy and full wound excision is currently the gold standard approach, but preparing the wound bed with negative pressure wound therapy (NPWT) can minimize edema and maximize dermal substitute take. The wounds were prepared using scrubbing and excision with Versajet® (Smith and Nephew) and the dermal substitute (Integra®, Integra Lifesciences Corporation) was applied. NPWT was used to improve vascularization prior to the application of a widely meshed, thinly harvested 3:1 graft in combination with RES to the vascularized dermal substitute recipient bed and all donor sites to reduce the risk of donor site morbidity.

Miss Murray discussed the case of a 22-year-old male who sustained a 70% TBSA burn injury. Full excision was performed immediately to prepare the wound bed, dermal substitute applied and edema was managed using NPWT. Neovascularization of the dermis was seen at 3 weeks, at which point a widely meshed autograft (3:1 except for the forearms and hands, 1.5:1) in combination with RES was applied. RES was also applied to donor sites and Miss Murray remarked that all the donor sites she treated were healed by 3 weeks. In the case Miss Murray presented, and representative of the patients she treated, the patient was 95% healed by 55 days, equating to 0.79 days healing per % TBSA. At 2 years post-treatment the patient is active, has had two small surgical releases and also received CO2 laser treatment to improve scarring.

Miss Murray believes that patients with complex soft tissue loss could benefit from this technique by optimizing wound closure using ReCell®. It is, however, important to give time for multi-organ failure and sepsis to subside, allowing adequate demarcation of the level of tissue to be lost, followed by staged excision of necrotic tissue and amputation where necessary. Skin substitutes underneath NPWT, the meticulous preparation of the neodermis and vigilant microbiological cover are essential. Only then is the wound ready for the mesh autograft in combination with RES approach.

References

1. Trim JE, Quick A. Regenerative Epithelial Suspension. Avita Medical, May 2015

2. Duke J, Wood F, Semmens J, et al. Rates of hospitalisations and mortality of older adults admitted with burn injuries in Western Australian from 1983 to 2008. Australas J Ageing. 2012;31(2):83–9

3. Graves C, Saffle J, Cochran A. Actual burn nutrition care practices: an update. J Burn Care Res. 2009;30(1):77-82

4. Lawrence A, Faraklas I, Watkins H, et al. Colloid administration normalizes resuscitation ratio and ameliorates "fluid creep". J Burn Care Res. 2010; 31(1):40-7

5. Hettiaratchy S, Dziewulski P. ABC of burns. Introduction. BMJ. 2004;328(7452):1366-8

6. Barrow RE, Spies M, Barrow LN, Herndon DN. Influence of demographics and inhalation injury on burn mortality in children. Burns. 2004;30:72–7

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10. Kurz N, Kahn SR, Abenhaim L, et al., eds. VEINES Task Force Report, The management of chronic venous disorders of the leg (CVDL): an evidence based report of an international task force. McGill University. Sir Mortimer B. Davis-Jewish General Hospital. Summary reports in: Angiology. 1997;48(1):59–66; and Int Angiol. 1999;18(2):83–102.

11. Smith JJ, Guest MG, Greenhalgh RM, Davies AH. Measuring the quality of life in patients with venous ulcers. J Vasc Surg. 2000; 31(4): 642-9

12. NICE. Diabetic foot problems: prevention and management. 2015 https://www.nice.org.uk/guidance/ng19/chapter/Introduction

13. Jackson PC, Wilks D, Rawlins J, Matteucci PL. Combined use of hyperbaric oxygen and sprayed keratinocyte suspension to tackle a difficult wound. Ann R Coll Surg Engl. 2014;96(6):e20-2

14. Enoch S, Leaper D. Basic science of wound healing. J Investigative Dermatology. 2007;27:514-525

15. Aust MC, Fernandes D, Kolokythas P, Kaplan HM, Vogt PM. Percutaneous collagen induction therapy: an alternative treatment for scars, wrinkles, and skin laxity. Plast Reconstr Surg. 2008; 121(4): 1421-9

16. Busch KH, Bender R, Walezko N, Aziz H, Altintas MA, Aust MC. Combination of medical needling and non-cultured autologous skin cell transplantation (ReNovaCell) for repigmentation of hypopigmented burn scars. Burns. 2016; [Epub ahead of print]

17. Komen L, VrijmanC,Tjin EPM, et al. Autologous cell suspension transplantation using acell extraction device in segmental vitiligo and piebaldism patients: arandomized controlled pilot study. J Am Acad Dermatol. 2015;73(1):170-2
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Regenerative Medicine

Journal, Future Science Group

Regenerative Medicine is an award-winning peer-reviewed journal, in print and web formats. The journal provides a forum to address the important challenges and advances in stem cell research and regenerative medicine, delivering this essential information in concise, clear and attractive article formats. Among other indexing services Regenerative Medicine is listed by MEDLINE/Index Medicus, EMBASE/Excerpta Medica, Chemical Abstracts, Science Citation Index Expanded™ (SciSearch®), Emcare, Biological Abstracts, BIOSIS Previews, Biotechnology Citation Index®, Journal Citation Reports/Science Edition®, Scopus® with an Impact Factor of 2.786 (2014). Each issue contains expertly drafted Reviews, Original Research articles, Perspectives, Editorials, topical insight from international leaders in their field, and additional added-value content. The Senior Editor of the journal is Professor Chris Mason, University College London. You can find out more about Regenerative Medicine at our website (www.future-science-group.com/journalprofile/regenerative-medicine/), where you can find the aims and scope of the journal and details of our international editorial board.
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