Skin tissue engineering has attained several clinical milestones making remarkable progress over the past decades. Skin is inhabited by a plethora of cells spatiotemporally arranged in a 3-dimensional (3D) matrix, creating a complex microenvironment of cell-matrix interactions. This complexity makes it difficult to mimic the native skin structure using conventional tissue engineering approaches. With the advent of newer fabrication strategies, the field is evolving rapidly. However, there is still a long way before an artificial skin substitute can fully mimic the functions and anatomical hierarchy of native human skin. The current focus of skin tissue engineers is primarily to develop a 3D construct that maintains the functionality of cultured cells in a guided manner over a period of time. While several natural and synthetic biopolymers have been translated, only partial clinical success is attained so far. Key challenges include the hierarchical complexity of skin anatomy; compositional mismatch in terms of material properties (stiffness, roughness, wettability) and degradation rate; biological complications like varied cell numbers, cell types, matrix gradients in each layer, varied immune responses, and varied methods of fabrication. In addition, with newer biomaterials being adopted for fabricating patient-specific skin substitutes, issues related to escalating processing costs, scalability, and stability of the constructs under in vivo conditions have raised some concerns. This review provides an overview of the field of skin regenerative medicine, existing clinical therapies, and limitations of the current techniques. We have further elaborated on the upcoming tissue engineering strategies that may serve as promising alternatives for generating functional skin substitutes, the pros and cons associated with each technique, and scope of their translational potential in the treatment of chronic skin ailments.

Candida tropicalis is a leading cause of invasive candidiasis in the Asia-Pacific region with reported crude mortality rates exceeding 50%. The rising prevalence of azole-resistant strains presents a significant clinical challenge. We analyzed 1,016 C. tropicalis clinical isolates collected over nine years from 27 hospitals across North India. Fluconazole resistance was detected in 5.1% ( n = 52) of isolates, with cross-resistance observed to voriconazole in 55.7% and itraconazole in 44.2% of isolates. Multilocus sequence typing (MLST) analysis of global 1,630 isolates including 208 Indian and whole-genome sequencing of 716 global isolates (139 Indian) confirmed the clonal emergence and persistence of azole-resistant MLST clade 4 strains in Indian hospitals. Phylogenomic analyses identified that Indian azole-resistant lineage was closely related to azole-resistant isolates from mainland China and Taiwan. The underlying mechanism of resistance involved hotspot mutations (Y132F) in the ERG11 gene along with its duplication, overexpression, and twofold high ergosterol content. Comparative transcriptomics of two clinical isolates exhibiting >512 fold difference in fluconazole susceptibility identified upregulation of virulence-associated genes, ALS7 gene (eightfold), SAP7 and SAP9 (1.6- and 2-fold, respectively) in azole-resistant isolate. Furthermore, azole-resistant isolates showed robust biofilm-associated metabolic activity (twofold), reduced β-glucan exposure, and greater survival in both neutrophil and macrophage killing assays. Notably, azole-resistant lineage exhibits several traits associated with adhesion and immune evasion that could possibly enable its spread in healthcare settings and signals the beginning of a greater spread of this clone. The urgent need for continuous genomic surveillance and antifungal stewardship is warranted to mitigate the spread of multidrug-resistant C. tropicalis . IMPORTANCE: Invasive fungal infections affect 6.5 million people annually and are associated with high mortality rates. Despite being the leading cause of invasive yeast infections in the Asia-Pacific, this is the first comprehensive study of Candida tropicalis from India documenting the emergence of azole-resistant clonal lineage (clade 4) in several hospitals in India. Azole resistance is driven by mutations, gene duplication, and overexpression of its target gene ERG11 . The Indian azole-resistant isolates showed high genetic relatedness with those from China. Also, resistant isolate showed overexpression of virulence-related genes and robust biofilm formation. Notably, reduced β-glucan exposure in fluconazole-resistant isolates may contribute to their decreased susceptibility to the innate immune system. Importantly, this study provides evidence for the emergence of azole-resistant C. tropicalis lineage in India, which exhibits several traits associated with adhesion and immune evasion that could possibly enable its spread in healthcare settings leading to a public health concern.

Fungal skin infections represent the fourth most prevalent disease globally, predominantly attributed to dermatophyte species such as Trichophyton . Nevertheless, sporadic instances of dermatophytosis may also arise from opportunistic, uncommon fungi. This study documents the association of keratinophilic fungi, Myriodontium keratinophilum and Aphanoascus verrucosus , with cases of dermatophytosis in Kashmir, North India. Internal transcribed spacer region sequencing of 64 isolates obtained from skin, hair, and nail samples of 62 patients identified 61% of isolates ( n = 39) as M. keratinophilum , followed by Trichophyton indotineae and A. verrucosus in 20% ( n = 13) and 19% ( n = 12) cases, respectively. Furthermore, the first hybrid de novo genome assembly of M. keratinophilum is reported in the present study. Genomic analysis of both M. keratinophilum and A. verrucosus species revealed median intra-species single nucleotide polymorphism (SNP) differences of 100 and 27, respectively, suggesting highly related strains in the patient population. De novo functional annotation identified a higher number of coding regions in M. keratinophilum compared to T. indotineae and A. verrucosus , including carbohydrate-active enzymes (CAZymes) exhibiting unique substrate affinities and subtilisin 3 ( SUB3 ) gene, previously implicated as a potential virulence gene in dermatophytes. Notably, in addition to all the multidrug transporters encoded by Trichophyton species, M. keratinophilum genome contains six putative ATP-binding cassette (ABC) transporters showing 40%–70% sequence similarity with the CDR1 gene. M. keratinophilum exhibited reduced susceptibility to multiple antifungals, including high minimum inhibitory concentrations (MICs) (>16 mg/L) against griseofulvin and itraconazole. Importantly, itraconazole is a primary therapeutic agent for terbinafine-resistant T. indotineae infections, underscoring the necessity for early and accurate identification and intervention of dermatophytic infections. IMPORTANCE: The study reports cases of dermatophytosis associated with two rare keratinophilic fungi, i.e., Myriodontium keratinophilum and Aphanoascus verrucosus . The cases mainly presented as tinea corporis and cruris, commonly caused by Trichophyton indotineae in the Indian subcontinent, which may remain undiagnosed due to a lack of molecular identification. Furthermore, the first-ever genome report of M. keratinophilum and its ab initio functional annotation is useful for further studies and management of opportunistic pathogens that exhibit reduced susceptibility towards itraconazole, the first-line drug of treatment for terbinafine-resistant T. indotineae infections. An early correct molecular identification of the etiologic agents of skin infections is warranted to tackle the new agents of dermatophytosis at the earliest stage.