In order to start the clinical trial it was necessary to show two key points: (1) that ADRCs from patients with burn are similar to those from non-burned patients and (2) that ADRCs improve burn wound healing.
- Comparison of ADRCs from Patients with Burn and Non-Burned Patients
In normal burn surgery the treatment requires excision of damaged tissue. This sometimes includes excising fat tissue immediately under the injured skin. Following permission from the patient, Cytori was able to obtain this fat tissue and use it to prepare ADRCs that could be compared to those ADRCs to those from non-burned patients. The results show that ADRCs prepared from deeper fat tissue obtained from directly under the burn exhibit the same composition and function as those from non-burned donors.
ADRCs from Patients with Burn (blue dots) and Non-Burned Patients (black dots) have same yield (left) and viability (right)
ADRCs from Burned Patients (top two rows) exhibit the same function as those from non-burned donors (bottom row)
- 2. ADRCs Improve Burn Wound Healing
Before starting a clinical trial in burn, Cytori scientists performed a number of studies to examine the safety and effectiveness of using ADRCs in burn. Because the skin of rodents (laboratory rats and mice) is very different than that in humans, these studies were performed in pigs, which have skin that is very similar to humans. All of these studies were performed in accordance with local and federal regulations. All studies were carefully monitored by licensed veterinarians and all animals received state-of-the-art care and pain control throughout each study. Performance of studies of this kind is a key and necessary step in obtaining FDA approval to perform a clinical trial in patients.
- 1. “Preclinical Assessment of Safety and Efficacy of Intravenous Delivery of Autologous Adipose-Derived Regenerative Cells(ADRCs) in the Treatment of Severe Thermal Burns using a Porcine Model” Foubert et al (2018) Burns (in press)
- In this paper the Investigators showed that intravenous delivery of ADRCs in animals with moderately large burn wounds (covering ~20% of the body surface area) led to improved healing of burn wounds treated with a meshed skin graft as well as improved healing of the skin graft donor site. Healing was evident in both the formation of new skin (epithelialization), the function of the new skin to act as a barrier to water loss, and in skin elasticity. This study also assessed the safety of this approach finding no negative effects on over 40 parameters that are used clinically to monitor the response to burn treatment. The study also allowed the Investigators to test different equipment for measuring the quality of healing of the skin graft. Lessons learned from this study were applied to RELIEF in terms of the treatment approach and to the use of equipment for measuring the elasticity, color, hardness, and function (water loss) of the healing skin. A summary (abstract) of this paper is available at the bottom of this page.
- 2. “Development of a combined radiation and full thickness burn injury minipig model to study the effects of uncultured adipose-derived regenerative cell therapy in wound healing” Foubert et al (2017) Int J Radiat Biol. 93(3):340-350
- In this paper the Investigators showed that intravenous delivery of ADRCs improved healing of burn wounds even when wound healing was impaired because of radiation exposure.
- 3. “Uncultured adipose-derived regenerative cells (ADRCs) seeded in collagen scaffold improves dermal regeneration, enhancing early vascularization and structural organization following thermal burns.” Foubert et al (2015) Burns. 2015 Nov;41(7):1504-16
- In this paper the Investigators showed that addition of ADRCs to a commonly-used skin substitute led to improved healing of burn wounds. This report led surgeons in Britain to treat two patients using the same skin substitute and ADRCs prepared using the Celution System. Results with these patients showed very good functional and cosmetic outcomes with high patient satisfaction.
- 4. “Autologous adipose-derived regenerative cell therapy modulates development of hypertrophic scarring in a red Duroc porcine model.” Foubert et al (2017) Stem Cell Res Ther. 8: 261
- In this paper the Investigators showed that treatment with ADRCs led to reduced scar formation in a particular type of pig that develops scars that are similar to those that develop in humans following burn injury.
- 5. “Adipose-Derived Regenerative Cell Therapy for Burn Wound Healing: A Comparison of Two Delivery Methods” Foubert et al (2015) Adv Wound Care 1; 5(7): 288–298
- In this paper the Investigators compared two different ways of delivering ADRCs to burn wounds. Both methods showed that ADRC-treatment led to faster formation of new skin (a process called “epithelialization”) along with reduced inflammation and greater production of new blood vessels (a process called “angiogenesis”)
- Cheng C et al. “Cell-Assisted Skin Grafting: Improving Texture and Elasticity of Skin Grafts through Autologous Cell
- Transplantation.” Plast Reconstr Surg 2016;137:58e–66e. doi:10.1097/PRS.0000000000001949.
Treatment with stromal vascular fraction cells (a research version of ADRCs) led to improved blood vessel formation (angiogenesis) and improved their resilience and elasticity of skin grafts after 1 month.
- Transplantation.” Plast Reconstr Surg 2016;137:58e–66e. doi:10.1097/PRS.0000000000001949.
- Atalay S et al. “Stromal vascular fraction improves deep partial thickness burn wound healing”. Burns 2014;40:1375–83. doi:10.1016/j.burns.2014.01.023.
- Treatment with stromal vascular fraction cells (a research version of ADRCs) led to improved blood vessel formation (angiogenesis) and reduced inflammation
- Eyuboglu et al. “The effect of adipose derived stromal vascular fraction on stasis zone in an experimental burn model”. Burns. 2018 Mar;44(2):386-396
- Treatment with stromal vascular fraction cells (a research version of ADRCs) led to reduced worsening over time (progression) of the damaged region immediately adjacent to a burn wound
- Cardoso et al “Adipose tissue stromal vascular fraction in the treatment of full thickness burns in rats” Acta Cir Bras. 2016 Sep;31(9):578-585
- Local injections of stromal vascular fraction cells (a research version of ADRCs) led to improved blood vessel formation (angiogenesis) and collagen deposition
Abstract from Foubert et al (2018)
ABSTRACT Objective: A number of studies have reported that application of autologous adipose-derived cell populations leads to improved outcome in different preclinical models of thermal burn injury. However, these studies were limited to assessment of relatively small injuries amounting to only ~2% of total body surface area (TBSA) in which the complications associated with large burns (e.g.: systemic inflammation and the need for fluid resuscitation) are absent. In anticipation of translating this approach to a clinical trial in which these complications would be present we applied a preclinical model that more closely resembles a patient with large thermal burn injury requiring skin grafting. Thus, the present study used a porcine model to investigate safety and efficacy of intravenous delivery of ADRCs in the treatment of a complex burn injury comprising ~20% TBSA and including both moderately deep (44%) partial and full thickness burns and the injury associated with skin graft harvest. Methods: Two pairs of full thickness and partial thickness burns involving in total ~20% TBSA were created on the back of Yorkshire pigs (n=15). Three days post-burn, full thickness wounds were excised and grafted with a 3:1 meshed autologous split thickness skin graft (STSG). Partial thickness wounds were not treated other than with dressings. Animals were then randomized to receive intravenous delivery of ADRCs (n=8) or vehicle control (n=7). Safety was assessed by monitoring systemic parameters (blood gases, hematology, and clinical chemistry) throughout the course of the study. Wound healing for both types of burn wound and for the skin graft donor sites was followed for 18 days using wound imaging, histology, and Trans-Epidermal Water Loss (TEWL; skin barrier function assessment). Results: No serious adverse events related to ADRC infusion were noted in any of the animals. Delivery of ADRCs appeared to be safe with none of the systemic safety parameters worsened compared to the control group. TEWL and histological analyses revealed that ADRC treatment was associated with significantly accelerated healing of skin graft (27.1% vs. 1.1% on day 5 post-grafting), donor site (52.8% vs. 33.1% on day 5 post-excision) and partial thickness burn (81.8% vs. 59.8% on day 18 post-treatment). Data also suggested that ADRC treatment improved parameters associated with skin graft elasticity Conclusions: This study demonstrated that intravenous delivery of autologous ADRCs appears to be a safe and feasible approach to the treatment of large burns and supports the use of ADRCs as an adjunct therapy to skin grafting in patients with severe burns.