Establishing Consensus of Best Practice for CEA Use in Treatment of Severe Burns: A US Burn Provider Delphi Study.

The goal of this study was to inform standards of best practice in the use of cultured epidermal autograft (CEA), manufactured in the United States, for the treatment of patients with severe burns. The study was designed using the modified Delphi technique, a method for structuring group communication among experts to promote the development of consensus-based recommendations. Known areas of variability related to the stages of CEA treatment were identified by literature review prior to the study and were confirmed through qualitative interview with the experts. The areas included Preoperative Planning/Surgical Planning, Immediate Postoperative Care, and Rehabilitation and Long-Term Care. A list of 22 questions was developed based on interviews with the experts, and a 3-round Delphi technique was used to establish consensus (≥80% agreement). Following 3 rounds (quantitative, qualitative, and virtual roundtable meeting) of the Delphi study, important guidance for the use of CEA treatment in severely burned patients gained consensus. Final key recommendations included minimum burn limit for CEA treatment (30%-50% TBSA), ideal biopsy timing (1-2 days), number of grafts (enough to cover; adjust 72 hours before application), use of dermal substrates (recommended) and wide meshed autograft underlay (recommended), optimal CEA drying time per day (open air >6 hours), slings used if CEA placed on extremities (recommended), dressing changes (performed every day, all at once, with all layers removed down to bridal veil), CEA backing removal (10-14 days after placement), heat lamps (can be used to aid the wound in drying, depending on clinical judgment), initial activity restrictions lifted (beginning 10 days after backing removal), compression garments (introduced at approximately 2 months post-CEA surgery), and lasers (CO2 laser can be introduced between 3 and 6 months post-CEA surgery).

Application and Management of Cultured Epidermal Autografts on Posterior Burns-A 5-Year, Multicenter, Retrospective Review of Outcomes.

Severe burns on the posterior trunk present a treatment challenge in that these surfaces bear the major portion of body weight, with shearing forces exerted when changing the patient from supine to prone position. In their high-volume center at Burn and Reconstructive Centers of America, the authors developed protocols for use of cultured epidermal autografts (CEAs) for coverage of large burns, including those specific to posterior burns. This paper describes techniques and approaches, including milestone timelines, to treat and manage these patients. Key factors for successful treatment begin with early development of a detailed surgical plan. Members of the trained team participate in the plan and understand standard procedures and any deviation. Patients are identified early for treatment with CEA so that a full thickness skin biopsy can be sent to the manufacturer for processing. Patients with >30% total body surface area (TBSA) burns are considered for CEA burn wound coverage due to the potential for conversion of superficial partial thickness to deep partial thickness or full thickness burns over hospitalization time. We also present the outcomes in patients with posterior trunk burns treated with CEA from 2016 to 2019 in three participating centers within our network. Data in 40 patients with mean TBSA of 56% demonstrated a high rate of successful CEA engraftment (83%), and overall survival rate (90%) following one or two applications with CEA and/or CEA + split thickness skin graft (STSG). Development of standard treatment protocols and surgical plans has enabled positive outcomes with CEA in severe burns including posterior burns.

Consensus on Rehabilitation Guidelines among Orthopedic Surgeons in the United States following Use of Third-Generation Articular Cartilage Repair (MACI) for Treatment of Knee Cartilage Lesions.

OBJECTIVE: The aim of this study was to evaluate levels of consensus in rehabilitation practices following MACI (autologous cultured chondrocytes on porcine collagen membrane) treatment based on the experience of an expert panel of U.S. orthopedic surgeons. DESIGN: A list of 24 questions was devised based on the current MACI rehabilitation protocol, literature review, and discussion with orthopedic surgeons. Known areas of variability were used to establish 4 consensus domains, stratified on lesion location (tibiofemoral [TF] or patellofemoral [PF]), including weightbearing (WB), range of motion (ROM), return to work/daily activities of living, and return to sports. A 3-step Delphi technique was used to establish consensus. RESULTS: Consensus (>75% agreement) was achieved on all 4 consensus domains. Time to full WB was agreed as immediate (with bracing) for PF patients (dependent on concomitant procedures), and 7 to 9 weeks in TF patients. A progression for ROM was agreed that allowed patients to reach 90° by week 4, with subsequent progression as tolerated. The panel estimated that the time to full ROM would be 7 to 9 weeks on average. A range of time was established for release to activities of daily living, work, and sports, dependent on lesion and patient characteristics. CONCLUSIONS: Good consensus was established among a panel of U.S. surgeons for rehabilitation practices following MACI treatment of knee cartilage lesions. The consensus of experts can aid surgeons and patients in the expectations and rehabilitation process as MACI surgery becomes more prevalent in the United States.

From bench to bedside: review of gene and cell-based therapies and the slow advancement into phase 3 clinical trials, with a focus on Aastrom's Ixmyelocel-T.

There is a large body of preclinical research demonstrating the efficacy of gene and cellular therapy for the potential treatment of severe (limb-threatening) peripheral arterial disease (PAD), including evidence for growth and transcription factors, monocytes, and mesenchymal stem cells. While preclinical research has advanced into early phase clinical trials in patients, few late-phase clinical trials have been conducted. The reasons for the slow progression of these therapies from bench to bedside are as complicated as the fields of gene and cellular therapies. The variety of tissue sources of stem cells (embryonic, adult bone marrow, umbilical cord, placenta, adipose tissue, etc.); autologous versus allogeneic donation; types of cells (hematopoietic, mesenchymal stromal, progenitor, and mixed populations); confusion and stigmatism by the public and patients regarding gene, protein, and stem cell therapy; scaling of manufacturing; and the changing regulatory environment all contribute to the small number of late phase (Phase 3) clinical trials and the lack of Food and Drug Administration (FDA) approvals. This review article provides an overview of the progression of research from gene therapy to the cellular therapy field as it applies to peripheral arterial disease, as well as the position of Aastrom's cellular therapy, ixmyelocel-T, within this field.

The Aastrom experience.

Aastrom Biosciences has developed a proprietary cell-processing technology that enables the manufacture of ixmyelocel-T, a patient-specific multicellular therapy expanded from a small sample of a patient's own bone marrow. Ixmyelocel-T is produced under current good manufacturing practices (cGMP) in a fully closed, automated system that expands mesenchymal stem cells (MSCs) and macrophages. While the cell types in ixmyelocel-T are the same as those found in the bone marrow, the numbers of MSCs and alternative macrophages are greater in ixmyelocel-T. We propose that the mixture of expanded MSCs and alternatively activated macrophages promote long-term tissue repair of ischemic tissue. The multiple cell types in ixmyelocel-T have a range of biological activities that are likely to contribute to a complex mechanism of action. Clinical trial data collected to date support the potential for ixmyelocel-T as an efficacious and safe treatment for ischemic cardiovascular indications, including critical limb ischemia (CLI) and a severe form of heart failure, dilated cardiomyopathy (DCM). The CLI clinical program has completed phase 2 and has reached concurrence with the Food and Drug Administration (FDA) on a phase 3 study (REVIVE) through the Special Protocol Assessment (SPA) process. The phase 3 study began screening patients in February 2012. The DCM clinical program will initiate phase 2b in 2012.