Pullulan-Collagen hydrogel wound dressing promotes dermal remodelling and wound healing compared to commercially available collagen dressings.

Biological scaffolds such as hydrogels provide an ideal, physio-mimetic of native extracellular matrix (ECM) that can improve wound healing outcomes after cutaneous injury. While most studies have focused on the benefits of hydrogels in accelerating wound healing, there are minimal data directly comparing different hydrogel material compositions. In this study, we utilized a splinted excisional wound model that recapitulates human-like wound healing in mice and treated wounds with three different collagen hydrogel dressings. We assessed the feasibility of applying each dressing and performed histologic and histopathologic analysis on the explanted scar tissues to assess variations in collagen architecture and alignment, as well as the tissue response. Our data indicate that the material properties of hydrogel dressings can significantly influence healing time, cellular response, and resulting architecture of healed scars. Specifically, our pullulan-collagen hydrogel dressing accelerated wound closure and promoted healed tissue with less dense, more randomly aligned, and shorter collagen fibres. Further understanding of how hydrogel properties affect the healing and resulting scar architecture of wounds may lead to novel insights and further optimization of the material properties of wound dressings.

Hematoxylin and Eosin Architecture Uncovers Clinically Divergent Niches in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the only cancers with an increasing incidence rate and is often associated with intra- and peri-tumoral scarring, referred to as desmoplasia. This scarring is highly heterogeneous in extracellular matrix (ECM) architecture and plays complex roles in both tumor biology and clinical outcomes that are not yet fully understood. Using hematoxylin and eosin (H&E), a routine histological stain utilized in existing clinical workflows, we quantified ECM architecture in 85 patient samples to assess relationships between desmoplastic architecture and clinical outcomes such as survival time and disease recurrence. By utilizing unsupervised machine learning to summarize a latent space across 147 local (e.g., fiber length, solidity) and global (e.g., fiber branching, porosity) H&E-based features, we identified a continuum of histological architectures that were associated with differences in both survival and recurrence. Furthermore, we mapped H&E architectures to a CO-Detection by indEXing (CODEX) reference atlas, revealing localized cell- and protein-based niches associated with outcome-positive versus outcome-negative scarring in the tumor microenvironment. Overall, our study utilizes standard H&E staining to uncover clinically relevant associations between desmoplastic organization and PDAC outcomes, offering a translatable pipeline to support prognostic decision-making and a blueprint of spatial-biological factors for modeling by tissue engineering methods.

The effect of foot orthoses on balance, foot pain and disability in elderly women with osteoporosis: a randomized clinical trial.

OBJECTIVE: To evaluate the effect of insoles with medial arch support and metatarsal pad on balance, foot pain and disability in elderly women with osteoporosis. METHODS: This was a randomized controlled clinical trial. Ninety-four elderly women (>60 years) with osteoporosis in treatment in the outpatient clinic of the Rheumatology Division of UNICAMP were randomly assigned to an intervention group (IG) with foot orthoses or to a control group (CG) without orthoses. The Berg Balance Scale (BBS), the Timed Up and Go test (TUG), the Manchester Foot Pain and Disability Index (MFPDI) and a numeric pain scale (NPS) were assessed at baseline and after 4 weeks. The chi-squared test, Fisher's exact test and Mann-Whitney test were applied to compare baseline values between the two groups. Repeated measures of analysis of variance followed by Tukey's test for multiple comparisons and the contrast profile test were used to compare the longitudinal measures. For numeric variable relationship analysis, the Spearman correlation coefficient was used. RESULTS: The groups were similar at baseline. Only subjects from the IG displayed improvements in balance (both BBS and TUG), foot pain (NPS) and disability (MFPDI) (P < 0.001). Minor adverse effects were noted. CONCLUSION: Foot orthoses were effective for improving balance and for reducing pain and disability in elderly women. Orthoses can be used as an adjuvant strategy to improve balance and to prevent falls in the elderly.

Allele-specific expression reveals genetic drivers of tissue regeneration in mice.

In adult mammals, skin wounds typically heal by scarring rather than through regeneration. In contrast, "super-healer" Murphy Roths Large (MRL) mice have the unusual ability to regenerate ear punch wounds; however, the molecular basis for this regeneration remains elusive. Here, in hybrid crosses between MRL and non-regenerating mice, we used allele-specific gene expression to identify cis-regulatory variation associated with ear regeneration. Analyzing three major cell populations (immune, fibroblast, and endothelial), we found that genes with cis-regulatory differences specifically in fibroblasts were associated with wound-healing pathways and also co-localized with quantitative trait loci for ear wound-healing. Ectopic treatment with one of these proteins, complement factor H (CFH), accelerated wound repair and induced regeneration in typically fibrotic wounds. Through single-cell RNA sequencing (RNA-seq), we observed that CFH treatment dramatically reduced immune cell recruitment to wounds, suggesting a potential mechanism for CFH's effect. Overall, our results provide insights into the molecular drivers of regeneration with potential clinical implications.

Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872-0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes.

Modulating Cellular Responses to Mechanical Forces to Promote Wound Regeneration.

Significance: Skin scarring poses a major biomedical burden for hundreds of millions of patients annually. However, this burden could be mitigated by therapies that promote wound regeneration, with full recovery of skin's normal adnexa, matrix ultrastructure, and mechanical strength. Recent Advances: The observation of wound regeneration in several mouse models suggests a retained capacity for postnatal mammalian skin to regenerate under the right conditions. Mechanical forces are a major contributor to skin fibrosis and a prime target for devices and therapeutics that could promote skin regeneration. Critical Issues: Wound-induced hair neogenesis, Acomys "spiny" mice, Murphy Roths Large mice, and mice treated with mechanotransduction inhibitors all show various degrees of wound regeneration. Comparison of regenerating wounds in these models against scarring wounds reveals differences in extracellular matrix interactions and in mechanosensitive activation of key signaling pathways, including Wnt, Sonic hedgehog, focal adhesion kinase, and Yes-associated protein. The advent of single-cell "omics" technologies has deepened this understanding and revealed that regeneration may recapitulate development in certain contexts, although it is unknown whether these mechanisms are relevant to healing in tight-skinned animals such as humans. Future Directions: While early findings in mice are promising, comparison across model systems is needed to resolve conflicting mechanisms and to identify conserved master regulators of skin regeneration. There also remains a dire need for studies on mechanomodulation of wounds in large, tight-skinned animals, such as red Duroc pigs, which better approximate human wound healing.

Partial Tendon Injury at the Tendon-to-Bone Enthesis Activates Skeletal Stem Cells.

The tendon enthesis plays a critical role in facilitating movement and reducing stress within joints. Partial enthesis injuries heal in a mechanically inferior manner and never achieve healthy tissue function. The cells responsible for tendon-to-bone healing remain incompletely characterized and their origin is unknown. Here, we evaluated the putative role of mouse skeletal stem cells (mSSCs) in the enthesis after partial-injury. We found that mSSCs were present at elevated levels within the enthesis following injury and that these cells downregulated TGFß signaling pathway elements at both the RNA and protein levels. Exogenous application of TGFß post-injury led to a reduced mSSC response and impaired healing, whereas treatment with a TGFß inhibitor (SB43154) resulted in a more robust mSSC response. Collectively, these data suggest that mSSCs may augment tendon-to-bone healing by dampening the effects of TGFß signaling within the mSSC niche.

Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing.

Regeneration is the holy grail of tissue repair, but skin injury typically yields fibrotic, non-functional scars. Developing pro-regenerative therapies requires rigorous understanding of the molecular progression from injury to fibrosis or regeneration. Here, we report the divergent molecular events driving skin wound cells toward scarring or regenerative fates. We profile scarring versus YAP-inhibition-induced wound regeneration at the transcriptional (single-cell RNA sequencing), protein (timsTOF proteomics), and tissue (extracellular matrix ultrastructural analysis) levels. Using cell-surface barcoding, we integrate these data to reveal fibrotic and regenerative "molecular trajectories" of healing. We show that disrupting YAP mechanotransduction yields regenerative repair by fibroblasts with activated Trps1 and Wnt signaling. Finally, via in vivo gene knockdown and overexpression in wounds, we identify Trps1 as a key regulatory gene that is necessary and partially sufficient for wound regeneration. Our findings serve as a multi-omic map of wound regeneration and could have therapeutic implications for pathologic fibroses.

Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring.

Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. Engrailed-1 lineage-positive fibroblasts (EPFs) are known to function in scarring, but Engrailed-1 lineage-negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating Engrailed-1 expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives Engrailed-1 activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents Engrailed-1 activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).

The effect of flat and textured insoles on the balance of primary care elderly people: a randomized controlled clinical trial.

BACKGROUND: Aging is associated with reduced postural stability and increased fall risk. Foot orthoses have been reported as an adjuvant intervention to improve balance by stimulating foot plantar mechanical receptors and thus increasing somatosensory input. PURPOSE: The aim of this study is to evaluate the effect of flat and textured insoles on the balance of primary care elderly people. DESIGN: Prospective, parallel, randomized, and single-blind trial. METHODS: A total of 100 subjects from a primary care unit, aged ≥65 years, were randomly assigned to intervention groups with flat insoles (n=33), textured insoles (n=33), or control group (n=34) without insoles. The Berg Balance Scale and the Timed Up and Go test were assessed at baseline and after 4 weeks. RESULTS: Improvements in the Berg Balance Scale and the Timed Up and Go test were noted only in intervention groups with insoles but not in control group. No significant difference was found between flat and textured insoles. Minor adverse effects were noted only in the group with textured insoles. CONCLUSION: The results suggest that foot orthoses (both flat and textured insoles) are effective in improving balance in primary care elderly people. They may represent a low-cost and high-availability adjuvant strategy to improve balance and prevent falls in this population.

Sensate composite calcaneal flap in leg amputation: a full terminal weight-bearing surface-experience in eight adult patients.

Despite modern reconstruction techniques and replantation, the preservation of a severely traumatised limb, or even a limb affected by a congenital malformation, usually gives poorer functional results compared with amputation and prosthetisation. The aim of this study was to describe a hind foot (including the calcaneum and fat pad) sensate flap with a surface that allows full terminal weight bearing in transtibial amputations in adults. Between June 2007 and September 2008, eight patients underwent leg amputations with a sensate composite calcaneal flap reconstruction of the stump. Patients consisted of four men and four women with a mean age of 46.5 (26-66) years. All amputations were unilateral. The mean follow-up was 28.3 (25-42) months. There were no complications. Calcaneum tibial fusion was observed in all patients in a mean time of 3.5 (3-4) months. A below-knee prosthesis was adapted at 16 weeks postoperatively in all cases, and no need for stump revision occurred in this series during the entire follow-up period. A transtibial amputation covered with a sensate plantar flap preserving the calcaneum was proposed. In theory, the anatomic structures spared in this technique provide a strong, full, weight-bearing terminal surface of the stump that will last a lifetime.

Amputaçäo dos membros inferiores na criança. Relato e experiência em 21 casos / Lower limb amputation in Children. Report and experience in 21 cases

Os autores apresentam os resultados de 21 pacientes, com idade média de 6 anos, submetidos à 26 amputações do membro inferior por malformações congênitas (14), infecções (06) e outras. Discute-se os procedimentos, as complicações, as vantagens e desvantagens de cada nível de amputação. Concluem que a amputação na criança continua sendo uma opção a ser considerada, principalmente por propiciar rápida recuperação funcional e social do paciente.