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1.
Burns ; 50(2): 424-432, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38087659

RESUMO

BACKGROUND: StrataGraft® (allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen-dsat) is an FDA-approved viable bioengineered allogeneic cellularized construct for adult patients with deep partial-thickness burns requiring surgery. We characterized the structural and functional properties of StrataGraft to improve product understanding by evaluating extracellular matrix (ECM) molecule distribution and secreted protein factor expression in vitro. METHODS: ECM protein expression was determined using indirect immunofluorescence on construct cross sections using commercial antibodies against collagen III, IV, VI, laminin-332, and decorin. Human collagen I expression was verified by enzyme-linked immunosorbent assay (ELISA) for collagen I C-terminal propeptide. Soluble protein factor secretion was quantified by multiplex biomarker assays and singleplex ELISA in conditioned media from meshed constructs. RESULTS: StrataGraft cellular components produced collagen I, collagen III, collagen VI, and decorin in patterns indicating an organized ECM. Distributions of collagen IV and laminin-332 indicated formation of basement membranes and dermal-epidermal junctions. Soluble protein factors were observed in the pg/cm2/h range from 1 h to the experiment end at 168 h. CONCLUSIONS: The organization of the ECM proteins was like human skin and the viable cellular components provided sustained secretion of soluble wound healing factors, making StrataGraft an attractive option for treating severe burns.


Assuntos
Queimaduras , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Animais , Camundongos , Proteínas da Matriz Extracelular , Decorina , Queimaduras/terapia , Cicatrização , Matriz Extracelular , Colágeno Tipo I , Calinina , Fibroblastos
2.
Burns ; 47(5): 1024-1037, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34099322

RESUMO

OBJECTIVE: This phase 3 study evaluated StrataGraft construct as a donor-site sparing alternative to autograft in patients with deep partial-thickness (DPT) burns. METHODS: Patients aged ≥18 years with 3-49% total body surface area (TBSA) thermal burns were enrolled. In each patient, 2 DPT areas (≤2000cm2 total) of comparable depth after excision were randomized to either cryopreserved StrataGraft or autograft. Coprimary endpoints were: the difference in percent area of StrataGraft treatment site and autograft treatment site autografted at Month 3 (M3), and the proportion of patients achieving durable wound closure of the StrataGraft site without autograft at M3. Safety assessments were performed in all patients. Efficacy and safety follow-up continued to 1 year. RESULTS: Seventy-one patients were enrolled. By M3, there was a 96% reduction in mean percent area of StrataGraft treatment sites that required autografting, compared with autograft treatment sites (4.3% vs 102.1%, respectively; P<.0001). StrataGraft treatment resulted in durable wound closure at M3 without autografting in 92% (95% CI: 85.6, 98.8; n/n 59/64) of patients for whom data were available. The most common StrataGraft-related adverse event was pruritus (15%). CONCLUSIONS: Both coprimary endpoints were achieved. StrataGraft may offer a new treatment for DPT burns to reduce the need for autografting. CLINICAL TRIAL IDENTIFIER: NCT03005106.


Assuntos
Queimaduras , Transplante de Pele , Adulto , Queimaduras/cirurgia , Humanos , Pele , Transplante Autólogo , Resultado do Tratamento , Cicatrização
3.
Burns ; 45(8): 1749-1758, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31416637

RESUMO

OBJECTIVE: This open-label, controlled, randomized study assessed the safety, tolerability, and efficacy of StrataGraft tissue compared to autograft in the treatment of deep partial-thickness (DPT) burns. METHODS: Thirty subjects with DPT thermal burns (3%-43% total body surface area) were treated with StrataGraft tissue as follows: cohort 1, ≤220 cm2 refrigerated tissue; cohort 2, ≤440 cm2 refrigerated tissue; and cohort 3, ≤440 cm2 cryopreserved tissue. On each subject, two comparable areas of DPT burn were randomized to receive StrataGraft tissue or autograft. Coprimary end points were the percent area of the StrataGraft tissue treatment site undergoing salvage autografting by Day 28 and wound closure of treatment sites by 3 months. RESULTS: By Day 28, no StrataGraft tissue treatment sites underwent autografting. By 3 months, 93% and 100% of the StrataGraft tissue and autograft treatment sites achieved complete wound closure, respectively. No significant differences in observer total and overall opinion POSAS scores between StrataGraft tissue and autograft treatment sites were observed at any timepoint. The most common adverse event was pruritus (17%). CONCLUSIONS: StrataGraft tissue treatment of DPT thermal burns reduced the need for autograft, resulted in wound closure and treatment-site cosmesis comparable to that of autograft, and was well tolerated.


Assuntos
Queimaduras/terapia , Reepitelização , Transplante de Pele , Pele Artificial , Engenharia Tecidual , Adulto , Queimaduras/patologia , Derme , Epiderme , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Prurido/etiologia , Terapia de Salvação , Pele , Transplante Autólogo , Resultado do Tratamento , Cicatrização
4.
Ann Surg ; 253(4): 672-83, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21475006

RESUMO

OBJECTIVE: The goal of this study was to assess the immunogenicity and antigenicity of StrataGraft skin tissue in a randomized phase I/II clinical trial for the temporary management of full-thickness skin loss. BACKGROUND: StrataGraft skin tissue consists of a dermal equivalent containing human dermal fibroblasts and a fully stratified, biologically active epidermis derived from Near-diploid Immortalized Keratinocyte S (NIKS) cells, a pathogen-free, long-lived, consistent, human keratinocyte progenitor. METHODS: Traumatic skin wounds often require temporary allograft coverage to stabilize the wound bed until autografting is possible. StrataGraft and cadaveric allograft were placed side by side on 15 patients with full-thickness skin defects for 1 week before autografting. Allografts were removed from the wound bed and examined for allogeneic immune responses. Immunohistochemistry and indirect immunofluorescence were used to assess tissue structure and cellular composition of allografts. In vitro lymphocyte proliferation assays, chromium-release assays, and development of antibodies were used to examine allogeneic responses. RESULTS: One week after patient exposure to allografts, there were no differences in the numbers of T or B lymphocytes or Langerhans cells present in StrataGraft skin substitute compared to cadaver allograft, the standard of care. Importantly, exposure to StrataGraft skin substitute did not induce the proliferation of patient peripheral blood mononuclear cells to NIKS keratinocytes or enhance cell-mediated lysis of NIKS keratinocytes in vitro. Similarly, no evidence of antibody generation targeted to the NIKS keratinocytes was seen. CONCLUSIONS: These findings indicate that StrataGraft tissue is well-tolerated and not acutely immunogenic in patients with traumatic skin wounds. Notably, exposure to StrataGraft did not increase patient sensitivity toward or elicit immune responses against the NIKS keratinocytes. We envision that this novel skin tissue technology will be widely used to facilitate the healing of traumatic cutaneous wounds.This study was registered at www.clinicaltrials.gov (NCT00618839).


Assuntos
Transplante de Pele/métodos , Pele Artificial , Pele/lesões , Lesões dos Tecidos Moles/cirurgia , Cicatrização/fisiologia , Adulto , Idoso , Cadáver , Procedimentos Cirúrgicos Dermatológicos , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Escala de Gravidade do Ferimento , Queratinócitos/transplante , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante de Pele/imunologia , Lesões dos Tecidos Moles/imunologia , Imunologia de Transplantes/fisiologia , Transplante Autólogo , Transplante Homólogo
5.
J Trauma ; 66(3): 866-73; discussion 873-4, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19276766

RESUMO

BACKGROUND: Large wounds often require temporary allograft placement to optimize the wound bed and prevent infection until permanent closure is feasible. We developed and clinically tested a second-generation living human skin substitute (StrataGraft). StrataGraft provides both a dermis and a fully-stratified, biologically-functional epidermis generated from a pathogen-free, long-lived human keratinocyte progenitor cell line, Neonatal Immortalized KeratinocyteS (NIKS). METHODS: Histology, electron microscopy, quantitative polymerase chain reaction, and bacterial growth in vitro were used to analyze human skin substitutes generated from primary human keratinocytes or NIKS cells. A phase I/II, National Institute of Health-funded, randomized, safety, and dose escalation trial was performed to assess autograft take in 15 patients 2 weeks after coverage with StrataGraft skin substitute or cryopreserved cadaver allograft. RESULTS: StrataGraft skin substitute exhibited a fully stratified epidermis with multilamellar lipid sheets and barrier function as well as robust human beta defensin-3 mRNA levels. Analysis of the primary endpoint in the clinical study revealed no differences in autograft take between wound sites pretreated with StrataGraft skin substitute or cadaver allograft. No StrataGraft-related adverse events or serious adverse events were observed. CONCLUSIONS: The major finding of this phase I/II clinical study is that performance of StrataGraft skin substitute was comparable to cadaver allograft for the temporary management of complex skin defects. StrataGraft skin substitute may also eliminate the risk for disease transmission associated with allograft tissue and offer additional protection to the wound bed through inherent antimicrobial properties. StrataGraft is a pathogen-free human skin substitute that is ideal for the management of severe skin wounds before autografting.


Assuntos
Transplante de Pele , Pele Artificial , Lesões dos Tecidos Moles/cirurgia , Cicatrização/fisiologia , Adulto , Cadáver , Desbridamento , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pele Artificial/microbiologia , Staphylococcus
6.
Tissue Eng Part A ; 14(5): 629-38, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18439105

RESUMO

For regenerative medicine to gain clinical acceptance, the effects of commonly used treatment regimens on bioengineered organs must be considered. The antibiotics mafenide acetate (mafenide) and neomycin plus polymyxin (neo/poly) are routinely used to irrigate postoperative skin grafts on contaminated wounds. The effects of these clinically used antibiotics were investigated using tissue-engineered human skin substitutes generated with primary human keratinocytes or the near-diploid human keratinocyte cell line, Near-diploid Immortal Keratinocytes. Following topical or dermal treatment, the skin substitutes were assayed for viability, tissue morphology, glycogen content, and the expression of active caspase 3. Mafenide, but not neo/poly, induced morphological and biochemical changes in tissue-engineered skin substitutes. Keratinocytes in all histological layers of mafenide-treated skin substitutes exhibited ballooning degeneration and glycogen depletion. Mafenide-treatment also triggered separation of basal keratinocytes from the underlying dermis. None of the antibiotic treatments induced apoptosis, as measured by active caspase 3 immunostaining. The results demonstrate that mafenide, but not neo/poly, is detrimental to the viability and structural integrity of tissue-engineered human skin substitutes. These findings highlight the need to identify treatment regimens that are compatible with and hence enable the therapeutic efficacy of first-generation bioengineered organs such as skin.


Assuntos
Antibacterianos/efeitos adversos , Pele Artificial , Engenharia Tecidual/métodos , Antibacterianos/uso terapêutico , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Glicogênio/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Mafenida/efeitos adversos , Mafenida/uso terapêutico , Teste de Materiais , Neomicina/uso terapêutico , Polimixinas/uso terapêutico
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