Supplemental Digital Content is available in the text.
Summary:
An autologous homologous skin construct (AHSC) has been developed for the repair and replacement of skin. It is created from a small, full-thickness harvest of healthy skin, which contains endogenous regenerative populations involved in native skin repair. A multicenter retrospective review of 15 wounds in 15 patients treated with AHSC was performed to evaluate the hypothesis that a single application could result in wound closure in a variety of wound types and that the resulting tissue would resemble native skin. Patients and wounds were selected and managed per provider’s discretion with no predefined inclusion, exclusion, or follow-up criteria. Dressings were changed weekly. Graft take and wound closure were documented during follow-up visits and imaged with a digital camera. Wound etiologies included 5 acute and chronic burn, 4 acute traumatic, and 6 chronic wounds. All wounds were closed with a single application of AHSC manufactured from a single tissue harvest. Median wound, harvest, and defect-to-harvest size ratio were 120 cm2 (range, 27–4800 cm2), 14 cm2 (range, 3–20 cm2), and 11:1 (range, 2:1–343:1), respectively. No adverse reactions with the full-thickness harvest site or the AHSC treatment site were reported. Average follow-up was 4 ± 3 months. An AHSC-treated area was biopsied, and a micrograph of the area was developed using immunofluorescent confocal microscopy, which demonstrated mature, full-thickness skin with nascent hair follicles and glands. This early clinical experience with ASHC suggests that it can close different wound types; however, additional studies are needed to verify this statement.
Cutaneous wounds are a significant health care burden worldwide, affecting up to 2% of the general population and >10% of the elderly, and are expected to increase, given the rise in population, age, diabetes, cardiovascular disease, and surgical interventions.1 An autologous homologous skin construct (AHSC; SkinTE; PolarityTE, Salt Lake City, Utah) cell-tissue product has been developed for the repair and replacement of skin.2–4 It is produced from a small piece of the patient’s healthy, full-thickness skin. The harvest is sent to a Federal Drug Administration–registered manufacturing facility. AHSC manufacturing involves the generation of microaggregates that retain the endogenous regenerative and supportive cells that are responsible for native skin repair.5,6 Processing in a physiologic media devoid of enzymes optimizes the aggregates for passive diffusion and initiates skin repair. AHSC is not cultured ex vivo, rather it is returned swiftly to the wound bed where the native wound environment can support the autologous aggregates, which implant and expand within the wound, facilitating closure from the inside out.4 We evaluated the hypothesis that a single application could result in wound closure in a variety of wound types. A multicenter, retrospective review of 15 wounds in 15 patients demonstrated that a single application of AHSC was able to close diverse wound types, including those refractory to advanced treatments, and the resulting tissue was similar to native skin.
METHODS
A multicenter, retrospective review of patients treated with AHSC between November 2017 and July 2018 was performed at 8 institutions. All patients or patient guardians were informed about the procedures and they provided written consent. Tissue biopsies were performed after obtaining informed consent from patients. Louisiana State University Health Science Center Institutional Review Board (#10326) approval was obtained for this retrospective study. This study meets the waiver criteria described in 45 Code of Federal Regulations (CFR) 164.512 (i) (2) (ii). Full-thickness skin was harvested from anatomic regions per provider’s and patient’s discretion. Tissue specimens were shipped in 0.9% sodium chloride at 4°C and processed into AHSC per manufacturer’s protocol at a Federal Drug Administration–registered facility by following Good Tissue Practice guidelines and returned at 4°C between 48 hours and up to 14 days following harvest per provider’s discretion for scheduling purposes. Wound beds were measured and prepared per standard of care at the time of deployment. AHSC was spread evenly across the wound bed and dressed with a nonadherent, nonabsorbent silicone dressing, which was secured with suture, staple, adhesive suture bandages, or bolstered with a negative pressure dressing or a petroleum-soaked gauze strip. Dressings were changed weekly until wound epithelialization. Patients and wounds were followed up at regular intervals per the providers’ discretion. Wounds were followed up with digital photography and assessed for closure by the provider at every visit, which was defined as complete epithelialization without drainage. A biopsy from patient 3 was fixed in 10% formalin and whole mount imaged with brightfield and immunofluorescent confocal microscopy (Leica TCS SP8, Wetzlar, Germany) following labeling with antibodies for pan-cytokeratin, platelet endothelial cell adhesion molecule (CD31), collagen I, and proliferation marker Ki-67 (Thermo Fisher Scientific, Waltham, Mass.).
RESULTS
Fifteen patients each had 1 wound treated with AHSC. The average follow-up was 4.0 ± 2.9 months. Wound etiologies included 5 burn injuries requiring skin grafting, 4 acute and traumatic injuries requiring tissue transfer, and 6 chronic wounds. (Table 1 and Fig. 1). The median age was 45 years (range, 7–72 years), with 9 (60%) patients being males. Average and median wound sizes were 461.3 and 120 cm2 (range, 27–4800 cm2), respectively. Average and median harvest sizes were 12.0 and 14.0 cm2 (range, 3–20 cm2), respectively. Average and median defect-to-harvest size ratios were 37.2:1 and 11.4:1 (range, 1.9:1 to 342.9:1), respectively. The most common previous treatment was split-thickness skin grafting (5 patients, 33%). All harvest sites were closed primarily, with no reported postclosure complications. All patients required a single application of AHSC with no repeat applications, and no additional procedures were required following AHSC treatment. All wounds had a complete epithelial closure within 8–12 weeks and full-thickness skin coverage by 5 months. Hematoxylin and eosin (H&E) staining of biopsy from patient 3 demonstrated a mature, stratified, cornified epithelium with melanin in the basement membrane and rete peg formation [see figure, Supplemental Digital Content 1, which displays regeneration of full-thickness skin. A, H&E staining of full-thickness skin biopsy taken from center of AHSC-treated area in patient 3 demonstrates full-thickness architecture, including rete pegs (arrow heads) as well as dermal appendages and vasculature (*). Scale bar = 100 µm. B, Ki-67 immunofluorescent labeling (red) demonstrating proliferating cells (nuclei: blue) associated with the basal epithelial progenitor cells (arrow heads) seen in region of interest. Dotted line indicates the surface of epithelium. Scale bar = 100 µm. Fluorescent probe labeling (blue: Hoechst 33342; red: actin) of full-thickness biopsy from Patient 3 demonstrated (C) complex vasculature, (D) glands (arrow heads), and (E) hair follicles (arrow heads) of AHSC-regenerated skin, http://links.lww.com/PRSGO/B373]. Immunofluorescent confocal microscopy demonstrated mature cytokeratin expressing epithelium, mature dermal collagen (Fig. 2), replicating basal keratinocytes, dermal capillary plexus, and nascent hair follicles and glands (see figure, Supplemental Digital Content 1, http://links.lww.com/PRSGO/B373).
Table 1.
Patient Demographics, Wound Etiologies, and Settings of Care
| Patient ID | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 |
| Age (y) | 19 | 47 | 10 | 69 | 45 | 10 | 8 | 7 | 23 | 66 | 50 | 31 | 72 | 56 | 70 |
| Sex | M | F | M | F | F | M | F | M | F | F | M | M | M | M | M |
| Mechanism of injury | Burn scald | Burn flame | Burn flame | Burn scald | Burn flame | Trauma avulsion–crush | Trauma avulsion–crush | Trauma avulsion | Acute surgical recon-struction | Chronic spider bite | Chronic DFU | Chronic 2/2 trauma MVC | Chronic VLU | Chronic pressure sore | Chronic wound 2/2 trauma |
| Defect type | Chronic | Chronic | Chronic | Chronic | Acute | Acute | Acute | Acute | Acute | Chronic | Chronic | Chronic | Chronic | Chronic | Chronic |
| Treatment site (anatomic) | RUE radial dorsal hand | (R) Lateral neck | (L) Chest | RUE syndactyly | BLE circum-ferential | LLE dorsal foot exposed tendon, bone, and joint | RLE calf, heel, dorsal foot; exposed tendon and muscle | LLE dorsal foot; exposed muscle, tendon, bone | LLE anterior lateral thigh flap donor site | LLE posterior calf | LLE TMA site | RLE exposed tibia | RLE anterior tibial; dorsal foot; exposed tendon | (R) heel exposed calcaneus | LLE lateral malleolus, exposed bone |
| Defect size (cm2) AHSC treated | 40 | 80 | 200 | 216 | 4800 | 80 | 435 | 120 | 378 | 30 | 27 | 200 | 225 | 36 | 50 |
| Harvest size (cm2) | 8 | 8 | 17.5 | 16 | 14 | 10 | 20 | 10 | 14 | 15 | 14 | 12 | 3 | 5 | 14 |
| Defect-to-harvest size ratio | 5:1 | 10:1 | 11.4:1 | 13.5:1 | 343:1 | 8:1 | 21.8:1 | 12:1 | 27:1 | 2:1 | 1.9:1 | 16.7:1 | 75:1 | 7.2:1 | 3.6:1 |
| Harvest location | Groin | Groin | Chest | Abdomen | Groin | Groin | Groin | Groin | Groin | Groin | Thigh | Groin | Abdomen | Calf | Abdomen |
| Harvest setting | Clinic | Clinic | Hospital | Clinic | Hospital | Hospital | Hospital | Hospital | Clinic | Clinic | Clinic | Clinic | Clinic | Hospital | Hospital |
| Previous treatments | STSG and SOC | STSG and SOC | STSG and SOC | STSG, Z-plasty, and SOC | Allograft and skin substitutes | NPWT (VAC) and advanced WCP | NPWT (VAC), advanced WCP | NPWT (VAC), advanced WCP | Advanced WCP | Collagen matrix + STSG, advanced WCP | TMA and free flap, advanced WCP | STSG ×2, SOC, NPWT, advanced WCP | SOC, advanced WCP | SOC, advanced WCP | SOC, advanced WCP |
BLE, bilateral lower extremity; DFU, diabetic foot ulcer; F, female; L, left; LLE, left lower extremity; M, male; MVC, motor vehicle crash; NPWT, negative pressure wound therapy; RUE, right upper extremity; R, right; RLE, right lower extremity; STSG, split-thickness skin grafting; SOC, standard of care; TMA, transmetatarsal amputation; VLU, venous leg ulcer; VAC, vacuum assisted closure; WCP, wound care products; Z-plasty, scar realignment.
Fig. 1.
Representative pictures of before and after treatment with an AHSC. Patient 15 with left chronic lateral malleolus wound before (A), and after 6 months (B) of AHSC treatment.
Fig. 2.
Immunofluorescent imaging of patient 3 biopsy from AHSC-treated area demonstrating full-thickness skin. Pan-cytokeratin (orange), collagen (green), and platelet endothelial cell adhesion molecule (CD31) (red) immunofluorescent labeling with 4′,6-diamidino-2-phenylindole (DAPI) nuclei labeling (blue) consistent with mature epithelium with rete peg formation (white arrow heads) and dermal architecture. Scale bar = 100 µm.
DISCUSSION
Cutaneous defects are a growing healthcare burden that can be challenging to treat. A novel AHSC manufactured from the patient’s healthy skin that retains the endogenous regenerative populations responsible for native wound repair was evaluated in a variety of wound types, including acute burn, burn reconstruction, and chronic wounds in 15 patients across 8 institutions. The AHSC was able to achieve closure within 3 months of a single application created from a small piece of skin with an average difference in harvest size to wound size greater than 1:30. Long-term tissue evaluation of the closed tissue in one patient demonstrated native-appearing, full-thickness skin with all layers of the epithelium, replicating basal keratinocytes, rete pegs, and a dermis with vascular plexus, nascent hair follicles, and glands. Utilization of AHSC was technically uncomplicated and could be performed in the clinic setting (Table 1) while taking advantage of established dressing protocols. Although the resultant skin appeared near normal in function, it was not cosmetically inconspicuous. Inherent patient factors relevant to tissue healing capabilities, such as age and medical comorbidities, likely affect the potential of the AHSC and were not adequately identified in this small retrospective case series. These early promising results support the need for additional studies to better understand the utility of the AHSC and how it may be incorporated into the wound reconstructive treatment ladder.
Supplementary Material
Footnotes
Published online 18 May 2020.
Disclosure: Drs. Mundinger, Smith, and Granick receive consulting fees from PolarityTE. Drs. Baetz, Labroo, Swanson, and Sopko are employees of PolarityTE. Dr. Armstrong is the study chair of clinical trials utilizing the autologous homologous skin construct. The other authors have no financial interest to declare.
Related Digital Media are available in the full-text version of the article on www.PRSGlobalOpen.com.
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