Treatment Of Deep Partial-thickness Burns Research Articles

89 Pooled Safety Analysis Evaluating Bioengineered Allogeneic Cellularized Construct in Patients with Deep Partial-thickness Thermal Burns

IntroductionAutograft (AG) is the standard of care treatment for deep burns but requires creation of a donor site wound prone to pain and scarring. Treatment with a bioengineered allogeneic cellularized construct (BACC) is an alternative approach that can reduce or eliminate the need for autografting. The BACC is a bilayer construct that was recently approved in the US for the treatment of adult deep partial-thickness (DPT) burns. Here, we report the analysis of pooled safety data from two open-label, randomized, controlled trials (STRATA2011 [NCT01437852] and STRATA2016 [NCT03005106]) that evaluated efficacy and safety of BACC versus autografting in patients with DPT burns.MethodsThe trials enrolled 101 patients aged ≥18 years with 3–49% total body surface area (TBSA) thermal burns. In each patient, two DPT areas on the torso or extremities were randomized to receive BACC or AG, where the mean total BACC dosage was 234.8 cm2 (range: 12.0–960.0 cm2). The safety endpoints assessed at each visit included: 1) treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs), and serious AEs (SAEs); 2) changes in immunologic responses (panel reactive antibodies [PRA], anti-bovine serum albumin [BSA] antibody response [STRATA2016 only]); 3) persistence of allogeneic DNA; and 4) laboratory exam and vital signs.ResultsEighty-seven patients (86.1%) experienced TEAEs, 30 patients (29.7%) experienced TRAEs, and 16 patients (15.8%) experienced SAEs. The most frequent TEAEs reported by ≥10% of patients in the pooled analysis were pruritus (n=31, 30.7%) and blister, hypertension, and hypertrophic scar (n=11, 10.9% each). The most frequent TRAEs (≥5% of patients) were pruritus (n=13, 12.9%) and blister (n=5, 5%). The most common SAEs were transplant (BACC or AG) failure, pneumonia, and deep vein thrombosis (n=2, 2% each), where only one SAE (impaired healing of moderate severity) was possibly related to BACC. One patient (1%) discontinued the trial due to a TEAE (traumatic brain injury). Two patients (2%) experienced SAEs that led to death, neither related to BACC. The number of patients with positive PRA values that were negative at baseline were 36 (38.7%) at Day 28 and 20 (22%) at Month 3. The number of patients with reactivity to HLA I class alleles found in the BACC increased from 4 (4%) at baseline to 39 (40.9%) at Day 28, then decreased to 22 (24.2%) at Month 3. No persistence of allogeneic DNA from the BACC was detected.ConclusionsBACC is well tolerated and is not associated with any unexpected SAEs or TEAEs. The safety profile at BACC treatment sites is similar to that at AG treatment sites. Thus, BACC may offer a safe alternative to autografting for the treatment of DPT burns.

658 Early Interventions with Autologous Skin Cell Suspension Leads to Positive Outcomes

Abstract Introduction Following initial stabilization, the primary goal of burn care is rapid wound closure to restore the barrier function and mechanical integrity of the skin. Time to wound closure is an important consideration when establishing the treatment plan, with a goal of re-epithelialization by 21 days to reduce the risks of hypertrophic scars (HTS), however, new research suggests that HTS can occur when healing is achieved as early as day 8. Early treatment of deep partial-thickness burns with autologous skin cell suspension (ASCS) was implemented at our burn center to achieve early wound closure and decrease hospital length of stay (LOS). Methods An IRB-approved, retrospective chart review of patients admitted between January 2020 to July 2020 was completed to evaluate the effectiveness of ASCS when applied as an early treatment defined as within 3 days of injury. Burn patients were excluded with delayed presentation >7 days, patients who only received ASCS to donor sites, and patients who died from unrelated comorbidities. Patients were excised to viable tissue. Patients with intact dermis were treated with ASCS. Patients without intact dermis were treated with ASCS and widely meshed autograft. Non-absorbent, small pore dressings were applied to the wound then covered with bismuth-petrolatum dressing, dry gauze, and compression bandage. Patients appropriate for discharge were followed-up in clinic for the first dressing change. Results Twenty-three patients were treated with ASCS utilizing this early intervention approach with 16 patients meeting inclusion criteria. Patients ranged from 15 months to 73 years of age and included 6 females and 10 males. The median total body surface area (TBSA) was 7.3% (range 2-23). Patients were taken for ASCS application between post burn day 0-3 (average 1.5). Average hospital LOS was 2.4 days. Operative dressings were removed between day 7-12 and >90% re-epithelization was noted between day 7-18 (mean 11). The mean LOS/%TBSA was 0.3. No patients required re-operation for closure of their wounds or reconstructive interventions for scarring. Conclusions Early excision of deep partial-thickness burns with application of ASCS allowed for healing to be achieved in a timely fashion. Implementation of an early operative approach to burn care allowed for a decrease in LOS and a decreased overall number of dressing changes.

Initial Experience With Autologous Skin Cell Suspension for Treatment of Deep Partial-Thickness Facial Burns.

Facial burns present a challenge in burn care, as hypertrophic scarring and dyspigmentation can interfere with patients' personal identities, ocular and oral functional outcomes, and have long-term deleterious effects. The purpose of this study is to evaluate our initial experience with non-cultured, autologous skin cell suspension (ASCS) for the treatment of deep partial-thickness (DPT) facial burns. Patients were enrolled at a single burn center during a multicenter, prospective, single-arm, observational study involving the compassionate use of ASCS for the treatment of large total BSA (TBSA) burns. Treatment decisions concerning facial burns were made by the senior author. Facial burns were initially excised and treated with allograft. The timing of ASCS application was influenced by an individual's clinical status; however, all patients were treated within 30 days of injury. Outcomes included subjective cosmetic parameters and the number of reoperations within 3 months. Five patients (4 males, 1 female) were treated with ASCS for DPT facial burns. Age ranged from 2.1 to 40.7 years (mean 18.2 ± 17.3 years). Average follow-up was 231.2 ± 173.1 days (range 63-424 days). Two patients required reoperation for partial graft loss within 3 months in areas of full-thickness injury. There were no major complications and one superficial hematoma. Healing and cosmetic outcomes were equivalent to, and sometimes substantially better than, outcomes typical of split-thickness autografting. Non-cultured, ASCS was successfully used to treat DPT facial burns containing confluent dermis with remarkable cosmetic outcomes. Treatment of DPT burns with ASCS may be an alternative to current treatments, particularly in patients prone to dyspigmentation, scarring sequelae, and with limited donor sites.

The Role of Autologous PRP on Deep Partial-Thickness Burn Wound Healing in Bama Pigs.

In this study, we aimed to evaluate the therapeutic effects of autologous platelet-rich plasma (PRP) on deep partial-thickness burns in Bama pigs. Deep partial-thickness burn wounds were created on the back of Bama pigs. The reepithelialization time was compared between the PRP and control groups. The mean score of Ki67 (+) cells and α-SMA (+) vessels, the mean thickness of epidermis and dermis of the healing wounds were determined via H&E staining and immunohistochemical assay. The levels of the growth factors epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) were examined by ELISA. Our data showed that the time to wound reepithelialization was shorter in the PRP group compared with the control group. The thickness of the epidermis was larger in the PRP group compared with the control group. On the 7th and 14th days after the treatment, the mean score of Ki67 (+) cells and α-SMA (+) vessels were higher in the PRP group compared with the control group. The PRP group showed higher levels of growth factors (EGF, bFGF, and VEGF) compared with the control group by ELISA. The results indicated that PRP could improve wound healing process of deep partial-thickness burns in Bama pigs. The PRP increased the thickness of epidermis of the healed wounds, cell proliferation, and angiogenesis. We demonstrated that applying PRP had a greater potential for the treatment of deep partial-thickness burns.

A dual deformable liposomal ointment functionalized with retinoic acid and epidermal growth factor for enhanced burn wound healing therapy.

An ointment containing retinoic acid deformable liposomes (TRA DLs) and epidermal growth factor cationic deformable liposomes (EGF CDLs) was prepared for the treatment of deep partial-thickness burns. The characterization tests confirmed both liposomes featured small particle sizes, high drug entrapment efficiencies and sustained drug release behavior. Compared with the free drug, TRA DLs and EGF CDLs exhibited superior skin permeation and remarkably increased drug deposition by 2.9 and 18.8 folds, respectively. Results on HaCaT cells indicated the combined application of two liposomes exerted a synergistic effect and prominently promoted cell proliferation and migration. Application of the dual liposomal ointment on a deep partial-thickness burn model stimulated wound closure (p < 0.001), promoted skin appendage formation and increased collagen production, thus improving healing quality. Finally, it was demonstrated that TRA significantly up-regulated the expression of EGFR and HB-EGF to enhance the therapeutic effect of EGF. Therefore, the dual liposomal ointment is a promising topical therapeutic for burn treatment.

Pirfenidone Ointment Modulates the Burn Wound Bed in C57BL/6 Mice by Suppressing Inflammatory Responses.

An inflammatory response is the normal response to a burn-induced injury. The burn-associated inflammation can lead to further tissue damage as the tissue tries to repair the damage. Prolonged or excessive inflammation is associated with increased fibrosis of burn wounds and the development of hypertrophic scars. The high incidence of hypertrophic scar formation is one of the many challenges to treating deep partial-thickness burns. Prophylactic treatment to improve burn-induced hypertrophic scarring is lacking. For this reason, we evaluated prophylactic treatment of deep partial-thickness burns with pirfenidone in C57BL/6 mice. Pirfenidone is an FDA-approved anti-fibrotic drug for systemic use in the treatment of idiopathic lung fibrosis and other fibrotic disorders. Additionally, pirfenidone has anti-inflammatory activity. We tested treatment efficacy of pirfenidone using a mouse model of deep partial-thickness burns. Inflammatory cytokines including IL-1β, IL-2, IL-6, IL-13, G-CSF, and MIP-1α, along with neutrophil infiltration, were significantly reduced in wounds when mice were treated during the inflammatory phase of burn wound healing. Additionally, pirfenidone significantly reduced expression of αSMA 12days after the induction of burns and modestly reduced hydroxyproline in 22-day-old burn wounds. Results show that pirfenidone treatment modulated the inflammatory response of the burn wound. The findings in this study indicate that further examination is required to validate the use of pirfenidone for prophylactic treatment to improve long-term outcomes of scarring and contracture in deep partial-thickness burn wounds.

Development of a Topical 48-H Release Formulation as an Anti-scarring Treatment for Deep Partial-Thickness Burns.

The purpose of this study was to develop pirfenidone (PF) ointment formulations for a dose finding study in the prophylactic treatment of deep partial-thickness burns in a mouse model. A preformulation study was performed to evaluate the solubility of PF in buffers and different solvents and its stability. Three different formulations containing 1, 3.5, and 6.5% w/w PF were prepared and optimized for their composition for testing in mice. Optimized formulations showed promising in vitro release profiles, in which 20-45% of PF was released in the first 7h and 70-90% released within 48h. The rheological properties of the ointment remained stable throughout storage at 25 ± 2°C/60% RH. Animal studies showed treatments of burn wounds during the inflammatory stage of wound healing with PF ointments at different drug concentrations had no adverse effects on reepithelization. Moreover, 6.5% PF ointment (F3) reduced the expression of pro-inflammatory cytokines IL-12p70 and TNFα. This study suggests that hydrocarbon base ointment could be a promising dosage form for topical delivery of PF in treatment of deep partial-thickness burns.

355 Regeneration of the Entire Human Epidermis by Transgenic Epidermal Stem Cell Transplants and its Implications for the Treatment of Burns

We recently performed the regeneration of almost an entire human epidermis by transplantation of genetically modified epidermal stem cells in a 7-year-old patient suffering from terminal Junctional Epidermolysis Bullosa (JEB). JEB is caused by mutations of genes encoding for basement membrane components, LAMB3 in this case, leading to severe skin lesions with often lethal outcome. These defects present in a similar fashion to deep partial-thickness burns with loss of epidermis but remaining dermal wound bed. Epidermal stem cells were procured via skin biopsy and transduced using a retroviral vector expressing the full-length LAMB3 cDNA. The transduced stem cells were then cultured using a modified culture protocol providing an optimal environment for the preservation of most potent epidermal stem cells, termed holoclones. We then transplanted 0,85m2 of autologous transgenic keratinocyte cultures after our patient had lost over 80% total body surface area of its epidermis. We performed a 2-year follow-up with clonal tracing and in-depth skin structure assessment using skin biopsies and optical coherence tomography. We also tested skin physiology parameters and mechanical stress resistance. We regenerated 80% of the child’s epidermis with autologous transgenic keratinocytes. Clonal tracing demonstrated, formally for the first time in humans, that the new epidermis was sustained by a finite number of holoclones. Two years after transplant, the patient demonstrated a high quality skin enabling a full range of motion, sebum production, and partial hair growth. Transepidermal water loss and skin elasticity were comparable to healthy skin. Sebum production was intact without the need for any more ointment application one year after transplant. In this study, we show that autologous transgenic keratinocyte cultures can regenerated an entire functional epidermis on a 7-year-old child after life-threatening loss of its original epidermis. We provide evidence for a high quality functional epidermis 2 years after transplantation that is sustained by a finite number of highly regenerative stem cells. Besides providing the first potential cure for JEB, this technology may enable a novel treatment of deep partial-thickness burns that is superior to split-thickness skin grafting or transplantation of regular cultured epidermal allografts.

Steel Wool-Aided Dermabrasion of Deep Partial-Thickness Burns.

Early tangential excision of the burn wound is essential for removal of necrotic tissue and promotion of burn wound healing process. However, the depth of the burn wound is not easily assessed during the tangential excision performed by hand-held dermatomes, and it may be possible to excise unburned vital dermis unnecessarily, which aids in primary epithelization of the burn wound by adnexal structures. We herein present early clinical results of steel wool-aided dermabrasion in patients with deep partial-thickness burns. This is a retrospective case study of 23 consecutive hospitalized patients with deep partial-thickness burns. All of the steel wool-aided dermabrasions were performed under general anesthesia within 48 hours after injury. Patients were excluded from the study if the admission was not within 24 hours after injury, and if the burn wound was entirely superficial partial- or full-thickness. Thirteen male and 10 female patients with a mean age of 26.2 ± 17.1 years were enrolled in the study. During the follow-up period, all of the patients had burn wounds primary epithelized on postburn day 15.1 ± 1.8, without any complications. None of the patients exhibited a mortal course, and redebridement or skin grafting of the previously dermabraded deep partial-thickness burn wounds were not required in any of the patients. Steel wool-aided dermabrasion is an easy, cost-effective, and reliable technique for the treatment of deep partial-thickness burns, which provides complete removal of necrotic tissue, preserves the vital dermis, reduces the requirement for skin grafting, and decreases length of hospital stay.

The Use of Hyalomatrix PA in the Treatment of Deep Partial-Thickness Burns

Since 2001, Hyalomatrix PA (Fidia Advanced Biopolymers, Abano Terme, Italy) has been used in our center on pediatric burned patients as a temporary dermal substitute to cover deep partial-thickness burns after dermabrasion. This "bridge" treatment was adopted to remove necrotic debris (dermabrasion) and to stimulate regeneration in a humid and protected environment (Hyalomatrix PA). We present results obtained with this approach. On the third to fifth day after admission, dermabrasion was practiced on deep burned areas, which were covered with Hyalomatrix PA. Change of dressings was performed every 7 days. On day 21, those areas still without signs of recovery were removed with classic escharectomy and covered with thin skin grafts. We treated 300 patients. Sixty-one percent needed only one dermabrasion treatment, 22.3% (67 patients) more than one, and 16.7% (50 patients) the classic escharectomy. A total of 83% of patients healed within 21 days. Our study suggests that the combination of dermabrasion with a temporary dermal substitute could be a good and feasible approach for treatment of deep partial-thickness burns. Prospective randomized studies are now necessary to compare our protocol with the gold standard treatment of topical dressings.