Disturbances in the levels of one-carbon (1C) metabolism metabolites have been associated with a wide variety of neuropsychiatric diseases. Cerebrospinal fluid (CSF) levels of homocysteine (Hcy) and the other 1C metabolites, nor their interrelatedness and putative determinants, have been studied extensively in a healthy population.Plasma and CSF samples from 100 individuals free from neuropsychiatric diseases were analyzed (55 male, 45 female; age 50±17 years). In blood, we measured plasma Hcy, serum folate and serum vitamin B12. In CSF, we measured total Hcy, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and 5-methyltetrahydrofolate (5-methylTHF). Highly selective analytical methods like liquid chromatography combined with either mass spectrometry or fluorescence detection were used.CSF Hcy was inversely correlated with CSF 5-methylTHF and positively with plasma Hcy, independent of serum folate status. CSF SAH correlated with age, lower CSF 5-methylTHF and higher CSF Hcy. CSF 5-methylTHF showed independent negative correlations with age and positive correlations with serum folate. CSF SAM did not correlate with any of the 1C metabolites.Aging is characterized by a reduction in CSF 5-methylTHF levels and increased CSF levels of the potentially neurotoxic transmethylation inhibitor SAH. CSF 5-methylTHF, which is itself determined in part by systemic folate status, is a powerful independent determinant of CSF levels of Hcy and SAH.

Limited donor sites and poor long-term outcomes with standard treatment for large skin defects remain a huge problem. An autologous, bilayered, laboratory-grown skin substitute (denovoSkin™) was developed to overcome this problem and has shown to be safe in ten pediatric patients in a phase I clinical trial after transplantation. The goal of this article is to report on 48 months long-term results. The pediatric participants of the phase I clinical trial were followed at yearly visits up to five years after transplantation. Safety parameters including occurrence of adverse events, possible deviations of vital signs and changes in concomitant therapy as well as additional parameters regarding skin stability, scar quality and tumor formation were assessed. Furthermore, scar maturation was photographically documented. From the ten patients treated with denovoSkin^TM in this phase I clinical trial, seven completed the five-year follow-up period. Skin substitutes continued to be deemed safe, remained stable and practically unchanged, with no sign of fragility, and no tumor formation at clinical examination. Scar quality, captured by applying the Patient and Observer Scar Assessment Scale, was evaluated as close to normal skin. Transplantation of this laboratory-grown skin substitute in children is to date considered safe and shows encouraging functional and aesthetical long-term results close to normal skin. These results are promising and highlight the potential of a life-saving therapy for large skin defects. A multicentre, prospective, randomized phase II clinical trial to further evaluate the safety and efficacy of this novel skin substitute is currently ongoing.

Autologous skin substitutes represent a promising advancement in the treatment of burn injuries, offering personalized solutions for patients with extensive skin loss. This white paper synthesizes the current knowledge on laboratory-generated autologous skin substitutes in Europe, incorporating expert opinions and legal considerations. The white paper examines the scientific principles underlying autologous skin substitute development, including cell sourcing, bioengineering techniques, and clinical applications. The regulatory framework governing the production and use of these advanced therapies in Europe is also examined, highlighting challenges in standardization, safety, and approval pathways. The text features expert insights that offer a real-world perspective on the clinical viability and translational hurdles of autologous skin substitutes. The findings highlight the potential of autologous skin substitutes to improve burn treatment outcomes while emphasizing the need for harmonized regulations to facilitate clinical implementation. Despite technological advancements, significant challenges persist, including production costs, scalability, and long-term efficacy. Another focus of this white paper are the legal changes, which have significantly impacted the production and availability of these technologies. The review concludes that while autologous skin substitutes hold great promise, further research, regulatory refinement, and interdisciplinary collaboration are essential to optimize their integration into clinical practice.

For burn surgery, major therapeutic challenges are shortage of autologous donor sites for split-thickness skin, and massive devastating scarring. We investigated the therapeutic role of denovoSkin™, a bio-engineered autologous skin, in a prospective, randomized, controlled phase IIb clinical trial compared to the gold standard the split thickness skin graft (STSG). Patients, ≥12 years, with deep partial and/or full-thickness burns requiring surgical wound coverage were enrolled at four sites in Switzerland, the Netherlands, and Italy. Two comparable skin defects (max. 98 cm² each) per patient were intra-patient randomized to denovoSkin™ (experimental) or autologous STSG (control) treatment. Safety assessments were performed in all patients. Primary efficacy endpoint was the ratio of biopsy size to grafted area with take 4 weeks post-grafting. The analyses of the primary efficacy variable were performed on the modified Full Analysis Set (mFAS) and the per protocol set (PPS) with the analysis on the mFAS as the primary analysis. Other efficacy endpoints included wound closure and scar quality. Efficacy and safety follow-ups were conducted up to 12 months post-grafting. The trial started in March 2018 and completed recruitment in July 2022 and is registered at clinicaltrials.gov (NCT03227146). 21 patients were enrolled between March 26, 2018, and July 26 2022. 13 patients were included in the PPS. There were no significant safety differences between denovoSkin™ and STSG. 164 serious adverse events were observed (81%). Only two (hematoma and partial skin necrosis) could be related to denovoSkin™. They rapidly healed spontaneously. The expansion ratio for denovoSkin™ versus STSG was 7·0 times larger for denovoSkin™ (p < 0·001). In the mFAS the mean expansion ratio for denovoSkin™ was 10·76 (SD 6·03), and for STSG it was 1·70 (SD 0·68). The mean ratio of the two expansion ratios (denovoSkin™/STSG) was 7·41 (SD 4·87). By month 3, experimental and control areas were fully epithelialized. Scar evaluation up to 12 months post-grafting revealed no clinically relevant scarring for denovoSkin™, but mostly hypertrophic scarring for STSG. DenovoSkin™ is a novel and safe treatment option for deep burns. It lessens the need for conventional grafting and so spares donor sites. In sharp contrast to STSG, denovoSkin™ grafting showed minimal scarring, a finding never evidenced before in a randomized trial. This study was financed by Wyss Zurich Translational Center (project “denovoSkin”) and CUTISS AG.

For pediatric patients with full-thickness burns, achieving adequate dermal regeneration is essential to prevent inelastic scars that may hinder growth. Traditional autologous split-thickness skin grafts alone often fail to restore the dermal layer adequately. This study evaluates the long-term effect of using a NovoSorb^® Biodegradable Temporizing Matrix (BTM) as a dermal scaffold in four pediatric patients, promoting dermal formation before autografting. Pediatric burn patients treated at the University Children’s Hospital Zurich between 2020 and 2022 underwent a two-step treatment involving NovoSorb^® BTM application, followed by autografting. Histological analysis, conducted through 22 punch biopsies taken up to 2.6 years post-application, demonstrated robust dermal reorganization, with mature epidermal regeneration and stable dermo-epidermal connections. Immunofluorescence staining showed rapid capillary ingrowth, while extracellular matrix components, including collagen and elastic fibers, gradually aligned over time, mimicking normal skin structure. By 2.6 years, the dermal layer displayed characteristics close to uninjured skin, with remnants of NovoSorb^® BTM degrading within five months post-application. This study suggests that NovoSorb^® BTM facilitates elastic scar formation, offering significant benefits for pediatric patients by reducing functional limitations associated with inelastic scarring.

Extensive full-thickness defects remain challenging to reconstruct, as various techniques used, such as split-thickness skin grafts, often result in donor site morbidity and functional and cosmetic scar sequelae. This study evaluated the safety and efficacy of denovoSkin™—a bio-engineered autologous dermo-epidermal skin graft consisting of patient-derived epidermal and dermal cells cultured within an extracellular matrix—compared to autologous split thickness skin grafts (STSG). Twenty-three patients (mean age 37.4 years; 65% male; 70% post-burn scars), received both denovoSkin™ and STSG on comparable wound areas. At 3 months, scar quality was significantly better for denovoSkin™ than for STSG (POSAS observer total score 23.4 vs 27.9; p = 0.008), with benefits maintained at 12 months. Elasticity parameters also consistently favored denovoSkin™, and the ratio of covered surface area to donor site was markedly higher (8.5 vs 0.9; p < 0.001). DenovoSkin™ is a safe and effective treatment for full-thickness skin defects, providing favorable long-term skin quality. Clinical Trial Registration: Clinicaltrials.gov NCT03394612.