Artem A. Trotsyuk, Ph.D.

All Publications

• Biomedical Data Science, Artificial Intelligence, and Ethics: Navigating Challenges in the Face of Explosive Growth. Annual review of biomedical data science Federico, C. A., Trotsyuk, A. A. 2024

  Abstract

  Advances in biomedical data science and artificial intelligence (AI) are profoundly changing the landscape of healthcare. This article reviews the ethical issues that arise with the development of AI technologies, including threats to privacy, data security, consent, and justice, as they relate to donors of tissue and data. It also considers broader societal obligations, including the importance of assessing the unintended consequences of AI research in biomedicine. In addition, this article highlights the challenge of rapid AI development against the backdrop of disparate regulatory frameworks, calling for a global approach to address concerns around data misuse, unintended surveillance, and the equitable distribution of AI's benefits and burdens. Finally, a number of potential solutions to these ethical quandaries are offered. Namely, the merits of advocating for a collaborative, informed, and flexible regulatory approach that balances innovation with individual rights and public welfare, fostering a trustworthy AI-driven healthcare ecosystem, are discussed.

  View details for DOI 10.1146/annurev-biodatasci-102623-104553

  View details for PubMedID 38598860

• Unreliable LLM Bioethics Assistants: Ethical and Pedagogical Risks. The American journal of bioethics : AJOB Goetz, L., Trengove, M., Trotsyuk, A., Federico, C. A. 2023; 23 (10): 89-91

  View details for DOI 10.1080/15265161.2023.2249843

  View details for PubMedID 37812124

• Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells. Nature biomedical engineering Padmanabhan, J., Chen, K., Sivaraj, D., Henn, D., Kuehlmann, B. A., Kussie, H. C., Zhao, E. T., Kahn, A., Bonham, C. A., Dohi, T., Beck, T. C., Trotsyuk, A. A., Stern-Buchbinder, Z. A., Than, P. A., Hosseini, H. S., Barrera, J. A., Magbual, N. J., Leeolou, M. C., Fischer, K. S., Tigchelaar, S. S., Lin, J. Q., Perrault, D. P., Borrelli, M. R., Kwon, S. H., Maan, Z. N., Dunn, J. C., Nazerali, R., Januszyk, M., Prantl, L., Gurtner, G. C. 2023

  Abstract

  Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellular and tissue levels can be induced in mice via the application of human-tissue-scale forces through a vibrating silicone implant. FBRs to such elevated extrinsic forces in the mice were also mediated by the activation of Rac2 signalling in a subpopulation of mechanoresponsive myeloid cells, which could be substantially reduced via the pharmacological or genetic inhibition of Rac2. Our findings provide an explanation for the stark differences in FBRs observed in small animals and humans, and have implications for the design and safety of implantable devices.

  View details for DOI 10.1038/s41551-023-01091-5

  View details for PubMedID 37749310

  View details for PubMedCentralID 2966551

• Stronger regulation of AI in biomedicine. Science translational medicine Trotsyuk, A. A., Federico, C. A., Cho, M. K., Altman, R. B., Magnus, D. 2023; 15 (713): eadi0336

  Abstract

  Regulatory agencies need to ensure the safety and equity of AI in biomedicine, and the time to do so is now.

  View details for DOI 10.1126/scitranslmed.adi0336

  View details for PubMedID 37703349

• Cas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing. Nature communications Henn, D., Zhao, D., Sivaraj, D., Trotsyuk, A., Bonham, C. A., Fischer, K. S., Kehl, T., Fehlmann, T., Greco, A. H., Kussie, H. C., Moortgat Illouz, S. E., Padmanabhan, J., Barrera, J. A., Kneser, U., Lenhof, H., Januszyk, M., Levi, B., Keller, A., Longaker, M. T., Chen, K., Qi, L. S., Gurtner, G. C. 2023; 14 (1): 4729

  Abstract

  Chronic wounds impose a significant healthcare burden to a broad patient population. Cell-based therapies, while having shown benefits for the treatment of chronic wounds, have not yet achieved widespread adoption into clinical practice. We developed a CRISPR/Cas9 approach to precisely edit murine dendritic cells to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing of tolerogenic dendritic cells, we identified N-myc downregulated gene 2 (Ndrg2), which marks a specific population of dendritic cell progenitors, as a promising target for CRISPR knockout. Ndrg2-knockout alters the transcriptomic profile of dendritic cells and preserves an immature cell state with a strong pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a therapeutic hydrogel for in vivo cell delivery and developed an effective translational approach for dendritic cell-based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in dendritic cells for treating various types of chronic wounds.

  View details for DOI 10.1038/s41467-023-40519-z

  View details for PubMedID 37550295

• Time From Authorization by the US Food and Drug Administration to Medicare Coverage for Novel Technologies. JAMA health forum Sexton, Z. A., Perl, J. R., Saul, H. R., Trotsyuk, A. A., Pietzsch, J. B., Ruggles, S. W., Nikolov, M. C., Schulman, K. A., Makower, J. 2023; 4 (8): e232260

  Abstract

  A wide variety of novel medical diagnostics and devices are determined safe and effective by the US Food and Drug Administration (FDA) each year, but to our knowledge the literature lacks evidence documenting how long it takes to establish new Medicare coverage for these technologies.To measure time from FDA authorization to at least nominal Medicare coverage for technologies requiring a new reimbursement pathway.In this cross-sectional study, public databases were used to associate each technology to billing codes, determine the effective date of each code and Medicare coverage decisions, and stratify by the maturity of the Medicare coverage. At least nominal coverage was defined as achievement of explicit coverage milestones through a national coverage determination, local coverage determinations by Medicare administrative contractors, or by implicit coverage aligned to a new billing code. Characterization by product type (acute treatment, chronic or ongoing treatment, diagnostic assay, and diagnostic device), manufacturer size, and evidence level were assessed for association with coverage achievement. The study included new product applications authorized by the FDA through the premarket approval pathway, the de novo pathway, or with breakthrough designation in the 510(k) pathway from January 1, 2016, to December 31, 2019. Data analysis took place between May 1, 2022, and December 31, 2022.Time from FDA authorization to the first coverage milestone.Among 281 identified technologies in the total sample, 64 (23%) were deemed novel technologies based on the absence of coverage determinations and/or the use of temporary or miscellaneous billing codes. Twenty-eight of 64 technologies (44%) successfully achieved explicit or implicit coverage following FDA authorization. The median time to at least nominal coverage for the analysis cohort was 5.7 years (90% CI, 4.4-NA years). Analysis of time-to-coverage data highlighted company size (log-rank P<.001) and product type (log-rank P = .01) as significant covariates associated with coverage achievement. No association was observed for technologies with level 1 evidence at FDA authorization and subsequent coverage milestone achievement (log-rank P = .40).In this cross-sectional study of 64 novel technologies, only 28 (44%) achieved coverage milestones over the study timeline. The several-year period observed to establish at least nominal coverage suggests existing coverage processes may affect timely reimbursement of new technologies.

  View details for DOI 10.1001/jamahealthforum.2023.2260

  View details for PubMedID 37540524

• Robotics in Plastic Surgery: It's Here. Plastic and reconstructive surgery Henn, D., Trotsyuk, A. A., Barrera, J. A., Sivaraj, D., Chen, K., Mittal, S., Mermin-Bunnell, A. M., Chattopadhyay, A., Larson, M. R., Kinney, B. M., Nachbar, J., TerKonda, S. P., Reddy, S., Jeffers, L., Sacks, J. M., Gurtner, G. C. 2023; 152 (1): 239-249

  Abstract

  Although robotic surgery has been routinely established in other surgical disciplines, robotic technologies have been less readily adopted in plastic surgery. Despite a strong demand for innovation and cutting-edge technology in plastic surgery, most reconstructive procedures, including microsurgery, have continued to necessitate an open approach. Recent advances in robotics and artificial intelligence, however, are gaining momentum and have shown significant promise to improve patient care in plastic surgery. These next-generation surgical robots have the potential to enable surgeons to perform complex procedures with greater precision, flexibility, and control than previously possible with conventional techniques. Successful integration of robotic technologies into clinical practice in plastic surgery requires achieving key milestones, including implementing appropriate surgical education and garnering patient trust.

  View details for DOI 10.1097/PRS.0000000000010270

  View details for PubMedID 37382921

• Blockchain, Information Security, Control, and Integrity - Who Is in Charge? Plastic and reconstructive surgery Barrera, J. A., Trotsyuk, A. A., Henn, D., Sivaraj, D., Chen, K., Mittal, S., Mermin-Bunnell, A. M., Larson, M. R., Padmanabhan, J., Kinney, B., Nachbar, J., Sacks, J., Terkonda, S. P., Jeffers, L., Gurtner, G. C. 2023

  Abstract

  Blockchain technology has attracted significant interest in recent years, most notably for its effect on global economics through the advent of cryptocurrency. Within the healthcare domain, blockchain technology has actively been explored as a tool for improving personal health data management, medical device security, and clinical trial management. Despite a strong demand for innovation and cutting-edge technology in Plastic Surgery, integration of Blockchain technologies within our specialty is still in its infancy. Recent advances and mainstream adoption of blockchain are gaining​ momentum​ and have shown significant promise for improving patient care and information management. In this article, we explain what defines a blockchain, and we discuss its history and potential applications in the field of Plastic Surgery. Existing evidence suggests that Blockchain can enable patient-centered data management, improve privacy, and provide additional safeguards against human error. Integration of Blockchain technology into clinical practice requires further research and development to demonstrate its safety and efficacy for patients and providers.

  View details for DOI 10.1097/PRS.0000000000010409

  View details for PubMedID 36917745

• Nitric oxide-releasing gel accelerates healing in a diabetic murine splinted excisional wound model. Frontiers in medicine Sivaraj, D., Noishiki, C., Kosaric, N., Kiwanuka, H., Kussie, H. C., Henn, D., Fischer, K. S., Trotsyuk, A. A., Greco, A. H., Kuehlmann, B. A., Quintero, F., Leeolou, M. C., Granoski, M. B., Hostler, A. C., Hahn, W. W., Januszyk, M., Murad, F., Chen, K., Gurtner, G. C. 2023; 10: 1060758

  Abstract

  According to the American Diabetes Association (ADA), 9-12 million patients suffer from chronic ulceration each year, costing the healthcare system over USD $25 billion annually. There is a significant unmet need for new and efficacious therapies to accelerate closure of non-healing wounds. Nitric Oxide (NO) levels typically increase rapidly after skin injury in the inflammatory phase and gradually diminish as wound healing progresses. The effect of increased NO concentration on promoting re-epithelization and wound closure has yet to be described in the context of diabetic wound healing.In this study, we investigated the effects of local administration of an NO-releasing gel on excisional wound healing in diabetic mice. The excisional wounds of each mouse received either NO-releasing gel or a control phosphate-buffered saline (PBS)-releasing gel treatment twice daily until complete wound closure.Topical administration of NO-gel significantly accelerated the rate of wound healing as compared with PBS-gel-treated mice during the later stages of healing. The treatment also promoted a more regenerative ECM architecture resulting in shorter, less dense, and more randomly aligned collagen fibers within the healed scars, similar to that of unwounded skin. Wound healing promoting factors fibronectin, TGF-β1, CD31, and VEGF were significantly elevated in NO vs. PBS-gel-treated wounds.The results of this work may have important clinical implications for the management of patients with non-healing wounds.

  View details for DOI 10.3389/fmed.2023.1060758

  View details for PubMedID 36999070

  View details for PubMedCentralID PMC10045479

• Sensor-enabled Multilayer Artificial Intelligence Analysis for Predictive Wound Healing and Real-Time Patient Monitoring Trotsyuk, A. A., Jing, S., Chen, K., Henn, D., Jiang, Y., Niu, S., Sivaraj, D., Nag, R., Snyder, M., bao, Z., Gurtner, G. C. WILEY. 2023: 268-269

  View details for Web of Science ID 001005693800060

• Interrogation of Wound Healing with Single Cell Analysis using a Wireless Smart Bandage Trotsyuk, A. A., Jiang, Y., Niu, S., Chen, K., Henn, D., Sivaraj, D., Bao, Z., Gurtner, G. C. WILEY. 2023: 270-271

  View details for Web of Science ID 001005693800064

• Outcomes of Biosynthetic and Synthetic Mesh in Ventral Hernia Repair. Plastic and reconstructive surgery. Global open Sivaraj, D., Fischer, K. S., Kim, T. S., Chen, K., Tigchelaar, S. S., Trotsyuk, A. A., Gurtner, G. C., Lee, G. K., Henn, D., Nazerali, R. S. 2022; 10 (12): e4707

  Abstract

  The introduction of mesh for reinforcement of ventral hernia repair (VHR) led to a significant reduction in hernia recurrence rates. However, it remains controversial whether synthetic or biologic mesh leads to superior outcomes. Recently, hybrid mesh consisting of reinforced biosynthetic ovine rumen (RBOR) has been developed and aims to combine the advantages of biologic and synthetic mesh; however, outcomes after VHR with RBOR have not yet been compared with the standard of care.Methods: We performed a retrospective analysis on 109 patients, who underwent VHR with RBOR (n = 50) or synthetic polypropylene mesh (n = 59). Demographic characteristics, comorbidities, postoperative complications, and recurrence rates were analyzed and compared between the groups. Multivariate logistic regression models were fit to assess associations of mesh type with overall complications and surgical site occurrence (SSO).Results: Patients who underwent VHR with RBOR were older (mean age 63.7 versus 58.8 years, P = 0.02) and had a higher rate of renal disease (28.0 versus 10.2%, P = 0.01) compared with patients with synthetic mesh. Despite an unfavorable risk profile, patients with RBOR had lower rates of SSO (16.0 versus 30.5%, P = 0.12) and similar hernia recurrence rates (4.0 versus 6.78%, P = 0.68) compared with patients with synthetic mesh. The use of synthetic mesh was significantly associated with higher odds for overall complications (3.78, P < 0.05) and SSO (3.87, P < 0.05).Conclusion: Compared with synthetic polypropylene mesh, the use of RBOR for VHR mitigates SSO while maintaining low hernia recurrence rates at 30-month follow-up.

  View details for DOI 10.1097/GOX.0000000000004707

  View details for PubMedID 36530858

• Healing chronic wounds with a wireless smart bandage with integrated sensors and stimulators NATURE BIOTECHNOLOGY Jiang, Y., Trotsyuk, A. A., Bao, Z. 2022

  View details for DOI 10.1038/s41587-022-01564-z

  View details for Web of Science ID 000887888900004

  View details for PubMedID 36424491

  View details for PubMedCentralID 5350204

• Wireless, closed-loop, smart bandage with integrated sensors and stimulators for advanced wound care and accelerated healing. Nature biotechnology Jiang, Y., Trotsyuk, A. A., Niu, S., Henn, D., Chen, K., Shih, C. C., Larson, M. R., Mermin-Bunnell, A. M., Mittal, S., Lai, J. C., Saberi, A., Beard, E., Jing, S., Zhong, D., Steele, S. R., Sun, K., Jain, T., Zhao, E., Neimeth, C. R., Viana, W. G., Tang, J., Sivaraj, D., Padmanabhan, J., Rodrigues, M., Perrault, D. P., Chattopadhyay, A., Maan, Z. N., Leeolou, M. C., Bonham, C. A., Kwon, S. H., Kussie, H. C., Fischer, K. S., Gurusankar, G., Liang, K., Zhang, K., Nag, R., Snyder, M. P., Januszyk, M., Gurtner, G. C., Bao, Z. 2022

  Abstract

  'Smart' bandages based on multimodal wearable devices could enable real-time physiological monitoring and active intervention to promote healing of chronic wounds. However, there has been limited development in incorporation of both sensors and stimulators for the current smart bandage technologies. Additionally, while adhesive electrodes are essential for robust signal transduction, detachment of existing adhesive dressings can lead to secondary damage to delicate wound tissues without switchable adhesion. Here we overcome these issues by developing a flexible bioelectronic system consisting of wirelessly powered, closed-loop sensing and stimulation circuits with skin-interfacing hydrogel electrodes capable of on-demand adhesion and detachment. In mice, we demonstrate that our wound care system can continuously monitor skin impedance and temperature and deliver electrical stimulation in response to the wound environment. Across preclinical wound models, the treatment group healed ~25% more rapidly and with ~50% enhancement in dermal remodeling compared with control. Further, we observed activation of proregenerative genes in monocyte and macrophage cell populations, which may enhance tissue regeneration, neovascularization and dermal recovery.

  View details for DOI 10.1038/s41587-022-01528-3

  View details for PubMedID 36424488

  View details for PubMedCentralID 5350204

• Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing Chen, K., Griffin, M., Henn, D., Bonham, C. A., Fischer, K., Padmanabhan, J., Trotsyuk, A. A., Sivaraj, D., Leeolou, M., Kussie, H. C., Huskins, S., Steele, S., Perrault, D., Longaker, M. T., Gurtner, G. C. WILEY. 2022: A22

  View details for Web of Science ID 000847524300054

• Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting. Science translational medicine Chen, K., Henn, D., Januszyk, M., Barrera, J. A., Noishiki, C., Bonham, C. A., Griffin, M., Tevlin, R., Carlomagno, T., Shannon, T., Fehlmann, T., Trotsyuk, A. A., Padmanabhan, J., Sivaraj, D., Perrault, D. P., Zamaleeva, A. I., Mays, C. J., Greco, A. H., Kwon, S. H., Leeolou, M. C., Huskins, S. L., Steele, S. R., Fischer, K. S., Kussie, H. C., Mittal, S., Mermin-Bunnell, A. M., Diaz Deleon, N. M., Lavin, C., Keller, A., Longaker, M. T., Gurtner, G. C. 2022; 14 (645): eabj9152

  Abstract

  Burns and other traumatic injuries represent a substantial biomedical burden. The current standard of care for deep injuries is autologous split-thickness skin grafting (STSG), which frequently results in contractures, abnormal pigmentation, and loss of biomechanical function. Currently, there are no effective therapies that can prevent fibrosis and contracture after STSG. Here, we have developed a clinically relevant porcine model of STSG and comprehensively characterized porcine cell populations involved in healing with single-cell resolution. We identified an up-regulation of proinflammatory and mechanotransduction signaling pathways in standard STSGs. Blocking mechanotransduction with a small-molecule focal adhesion kinase (FAK) inhibitor promoted healing, reduced contracture, mitigated scar formation, restored collagen architecture, and ultimately improved graft biomechanical properties. Acute mechanotransduction blockade up-regulated myeloid CXCL10-mediated anti-inflammation with decreased CXCL14-mediated myeloid and fibroblast recruitment. At later time points, mechanical signaling shifted fibroblasts toward profibrotic differentiation fates, and disruption of mechanotransduction modulated mesenchymal fibroblast differentiation states to block those responses, instead driving fibroblasts toward proregenerative, adipogenic states similar to unwounded skin. We then confirmed these two diverging fibroblast transcriptional trajectories in human skin, human scar, and a three-dimensional organotypic model of human skin. Together, pharmacological blockade of mechanotransduction markedly improved large animal healing after STSG by promoting both early, anti-inflammatory and late, regenerative transcriptional programs, resulting in healed tissue similar to unwounded skin. FAK inhibition could therefore supplement the current standard of care for traumatic and burn injuries.

  View details for DOI 10.1126/scitranslmed.abj9152

  View details for PubMedID 35584231

• Pullulan-Collagen Hydrogel Wound Dressing Promotes Dermal Remodeling and Wound Healing Compared to Commercially Available Collagen Dressings. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society Chen, K., Sivaraj, D., Davitt, M., Leeolou, M. C., Henn, D., Steele, S. R., Huskins, S. L., Trotsyuk, A. A., Kussie, H. C., Greco, A., Padmanabhan, J., Perrault, D. P., Zamaleeva, A. I., Longaker, M. T., Gurtner, G. C. 2022

  Abstract

  Biological scaffolds such as hydrogels provide an ideal, physio-mimetic of native 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 is 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 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 fibers. 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. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/wrr.13012

  View details for PubMedID 35384131

• Topological supramolecular network enabled high-conductivity, stretchable organic bioelectronics. Science (New York, N.Y.) Jiang, Y., Zhang, Z., Wang, Y. X., Li, D., Coen, C. T., Hwaun, E., Chen, G., Wu, H. C., Zhong, D., Niu, S., Wang, W., Saberi, A., Lai, J. C., Wu, Y., Wang, Y., Trotsyuk, A. A., Loh, K. Y., Shih, C. C., Xu, W., Liang, K., Zhang, K., Bai, Y., Gurusankar, G., Hu, W., Jia, W., Cheng, Z., Dauskardt, R. H., Gurtner, G. C., Tok, J. B., Deisseroth, K., Soltesz, I., Bao, Z. 2022; 375 (6587): 1411-1417

  Abstract

  Intrinsically stretchable bioelectronic devices based on soft and conducting organic materials have been regarded as the ideal interface for seamless and biocompatible integration with the human body. A remaining challenge is to combine high mechanical robustness with good electrical conduction, especially when patterned at small feature sizes. We develop a molecular engineering strategy based on a topological supramolecular network, which allows for the decoupling of competing effects from multiple molecular building blocks to meet complex requirements. We obtained simultaneously high conductivity and crack-onset strain in a physiological environment, with direct photopatternability down to the cellular scale. We further collected stable electromyography signals on soft and malleable octopus and performed localized neuromodulation down to single-nucleus precision for controlling organ-specific activities through the delicate brainstem.

  View details for DOI 10.1126/science.abj7564

  View details for PubMedID 35324282

• Enrichment of Nanofiber Hydrogel Composite with Fractionated Fat Promotes Regenerative Macrophage Polarization and Vascularization for Soft-Tissue Engineering. Plastic and reconstructive surgery Henn, D., Fischer, K. S., Chen, K., Greco, A. H., Martin, R. A., Sivaraj, D., Trotsyuk, A. A., Mao, H., Reddy, S. K., Kneser, U., Gurtner, G. C., Schmidt, V. J., Sacks, J. M. 2022; 149 (3): 433e-444e

  Abstract

  BACKGROUND: Fractionated fat has been shown to promote dermal regeneration; however, the use of fat grafting for reconstruction of soft-tissue defects is limited because of volume loss over time. The authors have developed a novel approach for engineering of vascularized soft tissue using an injectable nanofiber hydrogel composite enriched with fractionated fat.METHODS: Fractionated fat was generated by emulsification of groin fat pads from rats and mixed in a 3:1 ratio with nanofiber hydrogel composite (nanofiber hydrogel composite with fractionated fat). Nanofiber hydrogel composite with fractionated fat or nanofiber hydrogel composite alone was placed into isolation chambers together with arteriovenous loops, which were subcutaneously implanted into the groin of rats (n = 8 per group). After 21 days, animals were euthanized and systemically perfused with ink, and tissue was explanted for histologic analysis. Immunofluorescent staining and confocal laser scanning microscopy were used to quantify CD34+ progenitor cell and macrophage subpopulations.RESULTS: Nanofiber hydrogel composite with fractionated fat tissue maintained its shape without shrinking and showed a significantly stronger functional vascularization compared to composite alone after 21 days of implantation (mean vessel count, 833.5 ± 206.1 versus 296.5 ± 114.1; p = 0.04). Tissue heterogeneity and cell count were greater in composite with fractionated fat (mean cell count, 49,707 ± 18,491 versus 9263 ± 3790; p = 0.005), with a significantly higher number of progenitor cells and regenerative CD163+ macrophages compared to composite alone.CONCLUSIONS: Fractionated fat-enriched nanofiber hydrogel composite transforms into highly vascularized soft tissue over 21 days without signs of shrinking and promotes macrophage polarization toward regenerative phenotypes. Enrichment of injectable nanofiber hydrogel composite with fractionated fat represents a promising approach for durable reconstruction of soft-tissue defects.CLINICAL RELEVANCE STATEMENT: The authors' approach for tissue engineering may ultimately lay the groundwork for clinically relevant applications with the goal of generating large volumes of vascularized soft tissue for defect reconstruction without donor site morbidity.

  View details for DOI 10.1097/PRS.0000000000008872

  View details for PubMedID 35196680

• Mechanical Signaling Mediated by IQGAP1 Promotes Pathologic Foreign Body Response Sivaraj, D., Padmanabhan, J., Chen, K., Henn, D., Kussie, H. C., Leeolou, M. C., Trotsyuk, A. A., Fischer, K., Perrault, D., Gurtner, G. C. WILEY. 2022: A21

  View details for Web of Science ID 000763583000050

• Application of No Releasing Gel Increases Fibronectin, TGF-beta 1, and Accelerates Wound Healing in Diabetic Mice Noishiki, C., Sivaraj, D., Kosaric, N., Leeolou, M. C., Kussie, H. C., Kiwanuka, H., Henn, D., Fischer, K., Trotsyuk, A. A., Padmanabhan, J., Perrault, D., Murad, F., Chen, K., Gurtner, G. C. WILEY. 2022: A8

  View details for Web of Science ID 000763583000028

• Determining How Early Disruption Of Mechanotransduction Affects Acute Wound Healing Kussie, H. C., Sivaraj, D., Leeolou, M. C., Huskins, S. L., Steele, S., Henn, D., Trotsyuk, A. A., Gurtner, G. C., Chen, K. WILEY. 2022: A22

  View details for Web of Science ID 000763583000052

• Interactions Of Fibroblasts Versus Macrophages In An In Vitro Model Of Scar Formation And Wound Healing Huskins, S. L., Griffin, M., Steele, S., Thomas, B., Kussie, H. C., Sivaraj, D., Leeolou, M. C., Trotsyuk, A. A., Padmanabhan, J., Longaker, M. T., Gurtner, G. C., Chen, K. WILEY. 2022: A53-A54

  View details for Web of Science ID 000763583000115

• Pullulan-Collagen Hydrogel Wound Dressing Promotes Dermal Remodeling and Healing in an Excisional Wound Model Leeolou, M. C., Sivaraj, D., Davitt, M., Henn, D., Steele, S., Huskins, S. L., Trotsyuk, A. A., Kussie, H. C., Greco, A., Perrault, D., Padmanabhan, J., Longaker, M. T., Chen, K., Gurtner, G. C. WILEY. 2022: A24

  View details for Web of Science ID 000763583000056

• Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing Chen, K., Griffin, M., Henn, D., Bonham, C. A., Fischer, K., Padmanabhan, J., Trotsyuk, A. A., Sivaraj, D., Leeolou, M. C., Kussie, H. C., Huskins, S. L., Steele, S., Perrault, D., Longaker, M. T., Gurtner, G. C. WILEY. 2022: A5

  View details for Web of Science ID 000763583000021

• Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing Chen, K., Griffin, M., Henn, D., Bonham, C. A., Fischer, K., Padmanabhan, J., Trotsyuk, A. A., Sivaraj, D., Leeolou, M. C., Kussie, H. C., Huskins, S. L., Steele, S., Perrault, D., Longaker, M. T., Gurtner, G. C. WILEY. 2022: A31-A32

  View details for Web of Science ID 000763583000072

• Galvanotactic Smart Bandage for Chronic Wound Management and Tissue Regeneration Trotsyuk, A. A., Jiang, Y., Niu, S., Henn, D., Chen, K., Larson, M., Beard, E., Saberi, A., Sivaraj, D., Mermin-Bunnell, A., Mittal, S., Jing, S., Kwon, S., Bonham, C., Padmanabhan, J., Perrault, D., Leeolou, M. C., Januszyk, M., Bao, Z., Gurtner, G. C. WILEY. 2022: A36

  View details for Web of Science ID 000763583000080

• Allometric Tissue-Scale Forces Activate Mechanoresponsive Immune Cells To Drive Pathological Foreign Body Response To Biomedical Implants Padmanabhan, J., Chen, K., Sivaraj, D., Kuehlmann, B., Bonham, C., Dohi, T., Henn, D., Stern-Buchbinder, Z., Than, P., Hosseini, H., Barrera, J., Kussie, H., Magbual, N., Borrelli, M., Trotsyuk, A. A., Kwon, S., Dunn, J., Maan, Z., Januszyk, M., Prantl, L., Gurtner, G. C. WILEY. 2022: A19-A20

  View details for Web of Science ID 000763583000048

• IQGAP1-mediated mechanical signaling promotes the foreign body response to biomedical implants. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Sivaraj, D., Padmanabhan, J., Chen, K., Henn, D., Noishiki, C., Trotsyuk, A. A., Kussie, H. C., Leeolou, M. C., Magbual, N. J., Andrikopoulos, S., Perrault, D. P., Barrera, J. A., Januszyk, M., Gurtner, G. C. 2022; 36 (2): e22007

  Abstract

  The aim of this study was to further elucidate the molecular mechanisms that mediate pathologic foreign body response (FBR) to biomedical implants. The longevity of biomedical implants is limited by the FBR, which leads to implant failure and patient morbidity. Since the specific molecular mechanisms underlying fibrotic responses to biomedical implants have yet to be fully described, there are currently no targeted approaches to reduce pathologic FBR. We utilized proteomics analysis of human FBR samples to identify potential molecular targets for therapeutic inhibition of FBR. We then employed a murine model of FBR to further evaluate the role of this potential target. We performed histological and immunohistochemical analysis on the murine FBR capsule tissue, as well as single-cell RNA sequencing (scRNA-seq) on cells isolated from the capsules. We identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most promising of several targets, serving as a central molecular mediator in human and murine FBR compared to control subcutaneous tissue. IQGAP1-deficient mice displayed a significantly reduced FBR compared to wild-type mice as evidenced by lower levels of collagen deposition and maturity. Our scRNA-seq analysis revealed that decreasing IQGAP1 resulted in diminished transcription of mechanotransduction, inflammation, and fibrosis-related genes, which was confirmed on the protein level with immunofluorescent staining. The deficiency of IQGAP1 significantly attenuates FBR by deactivating downstream mechanotransduction signaling, inflammation, and fibrotic pathways. IQGAP1 may be a promising target for rational therapeutic design to mitigate pathologic FBR around biomedical implants.

  View details for DOI 10.1096/fj.202101354

  View details for PubMedID 35051300

• Inhibiting Fibroblast Mechanotransduction Modulates Severity of Idiopathic Pulmonary Fibrosis. Advances in wound care Trotsyuk, A. A., Chen, K., Kwon, S. H., Ma, K. C., Henn, D., Mermin-Bunnell, A. M., Mittal, S., Padmanabhan, J., Larson, M. R., Steele, S. R., Sivaraj, D., Bonham, C. A., Noishiki, C., Rodrigues, M., Jiang, Y., Jing, S., Niu, S., Chattopadhyay, A., Perrault, D. P., Leeolou, M. C., Fischer, K., Gurusankar, G., Choi Kussie, H., Wan, D. C., Januszyk, M., Longaker, M. T., Gurtner, G. C. 2021

  Abstract

  OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear to be important. Given the dynamic environment of the lung, we examined the significance of mechanotransduction on both inflammatory and fibrotic signaling during IPF.INNOVATION: Mechanotransduction pathways have not been thoroughly examined in the context of lung disease and pharmacologic approaches for IPF do not currently target these pathways. The interplay between mechanical strain and inflammation in pulmonary fibrosis remain incompletely understood.APPROACH: In this study, we used conditional KO mice to block mechanotransduction by knocking out FAK (Focal Adhesion Kinase) expression in fibroblasts, followed by induction of pulmonary fibrosis using bleomycin. We examined both normal human and human IPF fibroblasts and used immunohistochemistry, qRT-PCR, and Western Blot to evaluate the effects of FAK inhibition (FAKI) on modulating fibrotic and inflammatory genes.RESULTS: Our data indicate that deletion of FAK in mice reduces expression of fibrotic and inflammatory genes in lungs. Similarly, mechanical straining in normal human lung fibroblasts activates inflammatory and fibrotic pathways. FAK inhibition decreases these signals but has less effect on IPF fibroblasts as compared to normal human fibroblasts.CONCLUSION: Administering FAKI at early stages of fibrosis may attenuate the FAK-mediated fibrotic response pathway in IPF, potentially mediating disease progression.

  View details for DOI 10.1089/wound.2021.0077

  View details for PubMedID 34544267

• Mechanical Strain Drives Myeloid Cell Differentiation Toward Pro-Inflammatory Subpopulations. Advances in wound care Chen, K., Henn, D., Sivaraj, D., Bonham, C. A., Griffin, M., Choi Kussie, H., Padmanabhan, J., Trotsyuk, A. A., Wan, D. C., Januszyk, M., Longaker, M. T., Gurtner, G. C. 2021

  Abstract

  OBJECTIVE: After injury, humans and other mammals heal by forming fibrotic scar tissue with diminished function, and this healing process involves the dynamic interplay between resident cells within the skin and cells recruited from the circulation. Recent studies have provided mounting evidence that external mechanical forces stimulate intracellular signaling pathways to drive fibrotic processes.INNOVATION: While most studies have focused on studying mechanotransduction in fibroblasts, recent data suggest that mechanical stimulation may also shape the behavior of immune cells, referred to as "mechano-immunomodulation". However, the effect of mechanical strain on myeloid cell recruitment and differentiation remains poorly understood and has never been investigated at the single cell level.APPROACH: In this study, we utilized a three-dimensional (3D) in vitro culture system that permits the precise manipulation of mechanical strain applied to cells. We cultured myeloid cells and used single cell RNA-sequencing to interrogate the effects of strain on myeloid differentiation and transcriptional programming.RESULTS: Our data indicate that myeloid cells are indeed mechanoresponsive, with mechanical stress influencing myeloid differentiation. Mechanical strain also upregulated a cascade of inflammatory chemokines, most notably from the Ccl family.CONCLUSION: Further understanding of how mechanical stress affects myeloid cells in conjunction with other cell types in the complicated, multicellular milieu of wound healing may lead to novel insights and therapies for the treatment of fibrosis.

  View details for DOI 10.1089/wound.2021.0036

  View details for PubMedID 34278820

• Mechanical Activation Of Inflammation At The Implant-tissue Interface Underlies Pathological Foreign Body Response Padmanabhan, J., Chen, K., Bonham, C. A., Kuehlmann, B. A., Dohi, T., Henn, D., Stern-Buchbinder, Z. A., Than, P. A., Hosseini, H. S., Magbual, N. J., Borrelli, M., Sivaraj, D., Trotsyuk, A. A., Kwon, S., Maan, Z., Januszyk, M., Prantl, L., Gurtner, G. C. WILEY. 2021: A9

  View details for Web of Science ID 000650720500032

• CRISPR/Cas9 Editing Of Autologous Dendritic Cells To Enhance Angiogenesis And Wound Healing Henn, D., Zhao, D., Bonham, C. A., Chen, K., Greco, A. H., Padmanabhan, J., Sivaraj, D., Trotsyuk, A., Barrera, J. A., Januszyk, M., Qi, L., Gurtner, G. C. WILEY. 2021: A31-A32

  View details for Web of Science ID 000650720500079

• Disrupting Mechanotransduction Reduces Scar Formation And Restores Cellular Subpopulations In A Large Animal Model Of Skin Grafting Chen, K., Henn, D., Bonham, C. A., Noishiki, C., Barrera, J. A., Carlomagno, T. C., Shannon, T., Mays, C. J., Trotsyuk, A. A., Padmanabhan, J., Longaker, M. T., Januszyk, M., Gurtner, G. C. WILEY. 2021: A12-A13

  View details for Web of Science ID 000650720500039

• Adipose-derived stromal cells seeded in pullulan-collagen hydrogels improve healing in murine burns. Tissue engineering. Part A Barrera, J., Trotsyuk, A., Maan, Z. N., Bonham, C. A., Larson, M. R., Mittermiller, P. A., Henn, D., Chen, K., Mays, C. J., Mittal, S., Mermin-Bunnell, A. M., Sivaraj, D., Jing, S., Rodrigues, M., Kwon, S. H., Noishiki, C., Padmanabhan, J., Jiang, Y., Niu, S., Inayathullah, M., Rajadas, J., Januszyk, M., Gurtner, G. C. 2021

  Abstract

  Burn scars and scar contractures cause significant morbidity for patients. Recently, cell-based therapies have been proposed as an option for improving healing and reducing scarring after burn injury, through their known pro-angiogenic and immunomodulatory paracrine effects. Our lab has developed a pullulan-collagen hydrogel that, when seeded with mesenchymal stem cells (MSCs), improves cell viability and augments their pro-angiogenic capacity in vivo. Concurrently, recent research suggests that prospective isolation of cell subpopulations with desirable transcriptional profiles can be used to further improve cell-based therapies. In this study, we examined whether adipose-derived stem cell-seeded hydrogels could improve wound healing following thermal injury using a murine contact burn model. Partial thickness contact burns were created on the dorsum of mice. On days 5 and 10 following injury, burns were debrided and received either ASC-hydrogel, ASC injection alone, hydrogel alone, or no treatment. On days 10 and 25, burns were harvested for histologic and molecular analysis. This experiment was repeated using CD26+/CD55+ FACS-enriched ASCs to further evaluate the regenerative potential of ASCs in wound healing. ASC-hydrogel-treated burns demonstrated accelerated time to re-epithelialization, greater vascularity, and increased expression of the pro-angiogenic genes MCP-1, VEGF, and SDF-1 at both the mRNA and protein level. Expression of the pro-fibrotic gene Timp1 and pro-inflammatory gene Tnfa were down-regulated in ASC-hydrogel treated burns. ASC-hydrogel treated burns exhibited reduced scar area compared to hydrogel-treated and control wounds, with equivalent scar density. CD26+/CD55+ ASC-hydrogel treatment resulted in accelerated healing, increased dermal appendage count, and improved scar quality with a more reticular collagen pattern. Here we find that ASC-hydrogel therapy is effective for treating burns, with demonstrated pro-angiogenic, fibro-modulatory and immunomodulatory effects. Enrichment for CD26+/CD55+ ASCs has additive benefits for tissue architecture and collagen remodeling post-burn injury. Research is ongoing to further facilitate clinical translation of this promising therapeutic approach.

  View details for DOI 10.1089/ten.TEA.2020.0320

  View details for PubMedID 33789446

• Xenogeneic skin transplantation promotes angiogenesis and tissue regeneration through activated Trem2+ macrophages. Science advances Henn, D., Chen, K., Fehlmann, T., Trotsyuk, A. A., Sivaraj, D., Maan, Z. N., Bonham, C. A., Barrera, J. A., Mays, C. J., Greco, A. H., Moortgat Illouz, S. E., Lin, J. Q., Steele, S. R., Foster, D. S., Padmanabhan, J., Momeni, A., Nguyen, D., Wan, D. C., Kneser, U., Januszyk, M., Keller, A., Longaker, M. T., Gurtner, G. C. 2021; 7 (49): eabi4528

  Abstract

  [Figure: see text].

  View details for DOI 10.1126/sciadv.abi4528

  View details for PubMedID 34851663

• Hydrogel Scaffolds to Deliver Cell Therapies for Wound Healing. Frontiers in bioengineering and biotechnology Sivaraj, D., Chen, K., Chattopadhyay, A., Henn, D., Wu, W., Noishiki, C., Magbual, N. J., Mittal, S., Mermin-Bunnell, A. M., Bonham, C. A., Trotsyuk, A. A., Barrera, J. A., Padmanabhan, J., Januszyk, M., Gurtner, G. C. 2021; 9: 660145

  Abstract

  Cutaneous wounds are a growing global health burden as a result of an aging population coupled with increasing incidence of diabetes, obesity, and cancer. Cell-based approaches have been used to treat wounds due to their secretory, immunomodulatory, and regenerative effects, and recent studies have highlighted that delivery of stem cells may provide the most benefits. Delivering these cells to wounds with direct injection has been associated with low viability, transient retention, and overall poor efficacy. The use of bioactive scaffolds provides a promising method to improve cell therapy delivery. Specifically, hydrogels provide a physiologic microenvironment for transplanted cells, including mechanical support and protection from native immune cells, and cell-hydrogel interactions may be tailored based on specific tissue properties. In this review, we describe the current and future directions of various cell therapies and usage of hydrogels to deliver these cells for wound healing applications.

  View details for DOI 10.3389/fbioe.2021.660145

  View details for PubMedID 34012956

• Disrupting biological sensors of force promotes tissue regeneration in large organisms. Nature communications Chen, K., Kwon, S. H., Henn, D., Kuehlmann, B. A., Tevlin, R., Bonham, C. A., Griffin, M., Trotsyuk, A. A., Borrelli, M. R., Noishiki, C., Padmanabhan, J., Barrera, J. A., Maan, Z. N., Dohi, T., Mays, C. J., Greco, A. H., Sivaraj, D., Lin, J. Q., Fehlmann, T., Mermin-Bunnell, A. M., Mittal, S., Hu, M. S., Zamaleeva, A. I., Keller, A., Rajadas, J., Longaker, M. T., Januszyk, M., Gurtner, G. C. 2021; 12 (1): 5256

  Abstract

  Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.

  View details for DOI 10.1038/s41467-021-25410-z

  View details for PubMedID 34489407

• First reported case of Wohlfahrtiimonas chitiniclastica infection in California JAAD Case Reports Journal of the American Academy of Dermatology Case Reports Leelou, M. C., Perrault, D. P., Siravaj, D., Chang, A. S., Chen, K., Trotsyuk, A., Padmanabhan, J., Gurtner, G. C. 2021

  View details for DOI 10.1016/j.jdcr.2021.09.022

• Flexible smart bandage for wireless wound healing Trotsyuk, A. A., Jiang, Y., Niu, S., Larson, M., Beard, E., Saberi, A., Henn, D., Kwon, S., Bonham, C., Chen, K., Januszyk, M., Maan, Z., Barrera, J., Padmanabhan, J., Fischer, K. S., Bao, Z., Gurtner, G. C. WILEY. 2020: S24

  View details for Web of Science ID 000548418300050

• Cryopreserved human skin allografts promote angiogenesis and dermal regeneration in a murine model. International wound journal Henn, D. n., Chen, K. n., Maan, Z. N., Greco, A. H., Moortgat Illouz, S. E., Bonham, C. A., Barrera, J. A., Trotsyuk, A. A., Padmanabhan, J. n., Momeni, A. n., Wan, D. C., Nguyen, D. n., Januszyk, M. n., Gurtner, G. C. 2020

  Abstract

  Cryopreserved human skin allografts (CHSAs) are used for the coverage of major burns when donor sites for autografts are insufficiently available and have clinically shown beneficial effects on chronic non-healing wounds. However, the biologic mechanisms behind the regenerative properties of CHSA remain elusive. Furthermore, the impact of cryopreservation on the immunogenicity of CHSA has not been thoroughly investigated and raised concerns with regard to their clinical application. To investigate the importance and fate of living cells, we compared cryopreserved CHSA with human acellular dermal matrix (ADM) grafts in which living cells had been removed by chemical processing. Both grafts were subcutaneously implanted into C57BL/6 mice and explanted after 1, 3, 7, and 28 days (n = 5 per group). A sham surgery where no graft was implanted served as a control. Transmission electron microscopy (TEM) and flow cytometry were used to characterise the ultrastructure and cells within CHSA before implantation. Immunofluorescent staining of tissue sections was used to determine the immune reaction against the implanted grafts, the rate of apoptotic cells, and vascularisation as well as collagen content of the overlaying murine dermis. Digital quantification of collagen fibre alignment on tissue sections was used to quantify the degree of fibrosis within the murine dermis. A substantial population of live human cells with intact organelles was identified in CHSA prior to implantation. Subcutaneous pockets with implanted xenografts or ADMs healed without clinically apparent rejection and with a similar cellular immune response. CHSA implantation largely preserved the cellularity of the overlying murine dermis, whereas ADM was associated with a significantly higher rate of cellular apoptosis, identified by cleaved caspase-3 staining, and a stronger dendritic cell infiltration of the murine dermis. CHSA was found to induce a local angiogenic response, leading to significantly more vascularisation of the murine dermis compared with ADM and sham surgery on day 7. By day 28, aggregate collagen-1 content within the murine dermis was greater following CHSA implantation compared with ADM. Collagen fibre alignment of the murine dermis, correlating with the degree of fibrosis, was significantly greater in the ADM group, whereas CHSA maintained the characteristic basket weave pattern of the native murine dermis. Our data indicate that CHSAs promote angiogenesis and collagen-1 production without eliciting a significant fibrotic response in a xenograft model. These findings may provide insight into the beneficial effects clinically observed after treatment of chronic wounds and burns with CHSA.

  View details for DOI 10.1111/iwj.13349

  View details for PubMedID 32227459

• BIOMIMETIC ADIPIOSE STEM CELL DRESSING FOR SKIN REGENERATION Trotsyuk, A., Bonham, C. A., Rodrigues, M., Mittermiller, P., Rajadas, J., Inayathullah, M., Gurtner, G. WILEY. 2019: A4

  View details for Web of Science ID 000463117000011

• ACCELERATION OF WOUND HEALING WITH PHD2-AND MIR210-TARGETING OLIGONUCLEOTIDES Dallas, A., Trotsyuk, A., Ilves, H., Rodrigues, M., White, A., Gurtner, G., Johnston, B. H. WILEY. 2019: A36

  View details for Web of Science ID 000463117000158

• TOPICAL FOCAL ADHESION KINASE INHIBITOR PROMOTES SKIN REGENERATION AND SCAR PREVENTION IN A PRECLINICAL PORCINE MODEL Kwon, S., Kuehlmann, B., Dohi, T., Trotsyuk, A. A., Hu, M. S., Inayathullah, M., Rajadas, J., Longaker, M. T., Gurtner, G. C. WILEY. 2019: A11–A12

  View details for Web of Science ID 000463117000043

• Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds. Journal of controlled release : official journal of the Controlled Release Society Duscher, D. n., Trotsyuk, A. A., Maan, Z. N., Kwon, S. H., Rodrigues, M. n., Engel, K. n., Stern-Buchbinder, Z. A., Bonham, C. A., Whittam, A. J., Barrera, J. n., Hu, M. S., Inayathullah, M. n., Rajadas, J. n., Gurtner, G. C. 2019

  Abstract

  Chronic wounds remain a significant burden to both the healthcare system and individual patients, indicating an urgent need for new interventions. Deferoxamine (DFO), an iron-chelating agent clinically used to treat iron toxicity, has been shown to reduce oxidative stress and increase hypoxia-inducible factor-1 alpha (HIF-1α) activation, thereby promoting neovascularization and enhancing regeneration in chronic wounds. However due to its short half-life and adverse side effects associated with systemic absorption, there is a pressing need for targeted DFO delivery. We recently published a preclinical proof of concept drug delivery system (TDDS) which showed that transdermally applied DFO is effective in improving chronic wound healing. Here we present an enhanced TDDS (eTDDS) comprised exclusively of FDA-compliant constituents to optimize drug release and expedite clinical translation. We evaluate the eTDDS to the original TDDS and compare this with other commonly used delivery methods including DFO drip-on and polymer spray applications. The eTDDS displayed excellent physicochemical characteristics and markedly improved DFO delivery into human skin when compared to other topical application techniques. We demonstrate an accelerated wound healing response with the eTDDS treatment resulting in significantly increased wound vascularity, dermal thickness, collagen deposition and tensile strength. Together, these findings highlight the immediate clinical potential of DFO eTDDS to treating diabetic wounds. Further, the topical drug delivery platform has important implications for targeted pharmacologic therapy of a wide range of cutaneous diseases.

  View details for DOI 10.1016/j.jconrel.2019.07.009

  View details for PubMedID 31299261

• Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation JOURNAL OF INVESTIGATIVE DERMATOLOGY Ma, K., Kwon, S., Padmanabhan, J., Duscher, D., Trotsyuk, A. A., Dong, Y., Inayathullah, M., Rajadas, J., Gurtner, G. C. 2018; 138 (11): 2452–60

  View details for DOI 10.1016/j.jid.2018.04.034

  View details for Web of Science ID 000447794000026

• Deferoxamine Can Prevent Pressure Ulcers and Accelerate Healing in Aged Mice. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society Bonham, C. A., Rodrigues, M., Galvez, M., Trotsyuk, A., Stern-Buchbinder, Z., Inayathullah, M., Rajadas, J., Gurtner, G. C. 2018

  Abstract

  Chronic wounds are a significant medical and economic problem worldwide. Individuals over the age of 65 are particularly vulnerable to pressure ulcers and impaired wound healing. With this demographic growing rapidly there is a need for effective treatments. We have previously shown that defective hypoxia signaling through destabilization of the master hypoxia-inducible factor 1alpha (HIF-1alpha) underlies impairments in both aging and diabetic wound healing. To stabilize HIF-1alpha, we developed a transdermal delivery system of the FDA-approved small molecule deferoxamine (DFO) and found that transdermal DFO could both prevent and treat ulcers in diabetic mice. Here, we show that transdermal DFO can similarly prevent pressure ulcers and normalize aged wound healing. Enhanced wound healing by DFO is brought about by stabilization of HIF-1alpha and improvements in neovascularization. Transdermal DFO can be rapidly translated into the clinic and may represent a new approach to prevent and treat pressure ulcers in aged patients. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30152571

• RNA-Based Combination Therapy for Diabetic Wound Healing Johnston, B. H., Ilves, H., Trotsyuk, A., Rodrigues, M., White, A., Mandell, K., Hammond, P. T., Gurtner, G. C., Dallas, A. CELL PRESS. 2018: 38–39

  View details for Web of Science ID 000435342200078

• Deferoxamine can prevent pressure ulcers and accelerate healing in aged mice WOUND REPAIR AND REGENERATION Bonham, C. A., Rodrigues, M., Galvez, M., Trotsyuk, A., Stern-Buchbinder, Z., Inayathullah, M., Rajadas, J., Gurtner, G. C. 2018; 26 (3): 300–305

  View details for DOI 10.1111/wrr.12667

  View details for Web of Science ID 000451719400006

• Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation. The Journal of investigative dermatology Ma, K. n., Kwon, S. H., Padmanabhan, J. n., Duscher, D. n., Trotsyuk, A. A., Dong, Y. n., Inayathullah, M. n., Rajadas, J. n., Gurtner, G. C. 2018

  Abstract

  Formation of scars following wounding or trauma represents a significant healthcare burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, due to the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries. To address this issue, we have developed a pullulan collagen-based hydrogel to deliver FAKI to excisional and burn wounds in mice. Specifically, two distinct drug-laden hydrogels were developed for rapid or sustained release of FAKI for treatment of burn wounds and excisional wounds, respectively. Controlled delivery of FAKI via pullulan collagen hydrogels accelerated wound healing, reduced collagen deposition and activation of scar forming myofibroblasts in both wound healing models. Our study highlights a biomaterial-based drug delivery approach for wound and scar management that has significant translational implications.

  View details for PubMedID 29775632

• Acceleration of Diabetic Wound Healing with PHD2- and miR-210-targeting Oligonucleotides. Tissue engineering. Part A Dallas, A. n., Trotsyuk, A. n., Ilves, H. n., Bonham, C. A., Rodrigues, M. n., Engel, K. n., Barrera, J. A., Kosaric, N. n., Stern-Buchbinder, Z. A., White, A. n., Mandell, K. J., Hammond, P. n., Mansbridge, J. N., Jayasena, S. n., Gurtner, G. C., Johnston, B. H. 2018

  Abstract

  [PLACEHOLDER].

  View details for PubMedID 29644938

• Allogeneic Cd26/Cd55 Cell Therapy for Treating Burn Wounds Trotsyuk, A., Rodrigues, M., Bonham, C., Mittermiller, P., Gurtner, G. WILEY. 2018: A9

  View details for Web of Science ID 000430308600032

• Transdermal Deferoxamine Enhances Wound Healing in Aged Mice Bonham, C. A., Rodrigues, M., Trotsyuk, A., Stern-Buchbinder, Z., Inayathullah, M., Rajadas, J., Gurtner, G. C. WILEY. 2018: A10

  View details for Web of Science ID 000430308600036

• Identification of cancer stem cell subpopulations of CD34(+) PLC/PRF/5 that result in three types of human liver carcinomas. Stem cells and development Park, S. C., Nguyen, N. T., Eun, J. R., Zhang, Y., Jung, Y. J., Tschudy-Seney, B., Trotsyuk, A., Lam, A., Ramsamooj, R., Zhang, Y., Theise, N. D., Zern, M. A., Duan, Y. 2015; 24 (8): 1008-1021

  Abstract

  CD34(+) stem cells play an important role during liver development and regeneration. Thus, we hypothesized that some human liver carcinomas (HLCs) might be derived from transformed CD34(+) stem cells. Here, we determined that a population of CD34(+) cells isolated from PLC/PRF/5 hepatoma cells (PLC) appears to function as liver cancer stem cells (LCSCs) by forming HLCs in immunodeficient mice with as few as 100 cells. Moreover, the CD34(+) PLC subpopulation cells had an advantage over CD34(-) PLCs at initiating tumors. Three types of HLCs were generated from CD34(+) PLC: hepatocellular carcinomas (HCCs); cholangiocarcinomas (CC); and combined hepatocellular cholangiocarcinomas (CHCs). Tumors formed in mice transplanted with 12 subpopulations and 6 progeny subpopulations of CD34(+) PLC cells. Interestingly, progenies with certain surface antigens (CD133, CD44, CD90, or EPCAM) predominantly yielded HCCs. CD34(+) PLCs that also expressed OV6 and their progeny OV6(+) cells primarily produced CHC and CC. This represents the first experiment to demonstrate that the OV6(+) antigen is associated with human CHC and CC. CD34(+) PLCs that also expressed CD31 and their progeny CD31(+) cells formed CHCs. Gene expression patterns and tumor cell populations from all xenografts exhibited diverse patterns, indicating that tumor-initiating cells (TICs) with distinct antigenic profiles contribute to cancer cell heterogeneity. Therefore, we identified CD34(+) PLC cells functioning as LCSCs generating three types of HLCs. Eighteen subpopulations from one origin had the capacity independently to initiate tumors, thus functioning as TICs. This finding has broad implications for better understanding of the multistep model of tumor initiation and progression. Our finding also indicates that CD34(+) PLCs that also express OV6 or CD31 result in types of HLCs. This is the first report that PLC/PRF/5 subpopulations expressing CD34 in combination with particular antigens defines categories of HLCs, implicating a diversity of origins for HLC.

  View details for DOI 10.1089/scd.2014.0405

  View details for PubMedID 25519836

  View details for PubMedCentralID PMC4390116

• Human liver carcinomas originated from CD34+ hematopoietic precursors Hepatology Park, S., Nguyen, N. X., Zeng, C., Tschudy-Seney, B., Eun, J., Trotsyuk, A., Lam, A., Ramsamooj, R., Zern, M., Duan, Y. 2012: 56():807A–808A