Michael Longaker, Postdoctoral Faculty Sponsor
Michael Longaker, Postdoctoral Research Mentor
Bioprinted Hydrogels for Fibrosis and Wound Healing: Treatment and Modeling.
Gels (Basel, Switzerland)
2022; 9 (1)
Three-dimensional (3D) printing has been used to fabricate biomaterial scaffolds with finely controlled physical architecture and user-defined patterning of biological ligands. Excitingly, recent advances in bioprinting have enabled the development of highly biomimetic hydrogels for the treatment of fibrosis and the promotion of wound healing. Bioprinted hydrogels offer more accurate spatial recapitulation of the biochemical and biophysical cues that inhibit fibrosis and promote tissue regeneration, augmenting the therapeutic potential of hydrogel-based therapies. Accordingly, bioprinted hydrogels have been used for the treatment of fibrosis in a diverse array of tissues and organs, including the skin, heart, and endometrium. Furthermore, bioprinted hydrogels have been utilized for the healing of both acute and chronic wounds, which present unique biological microenvironments. In addition to these therapeutic applications, hydrogel bioprinting has been used to generate in vitro models of fibrosis in a variety of soft tissues such as the skin, heart, and liver, enabling high-throughput drug screening and tissue analysis at relatively low cost. As biological research begins to uncover the spatial biological features that underlie fibrosis and wound healing, bioprinting offers a powerful toolkit to recapitulate spatially defined pro-regenerative and anti-fibrotic cues for an array of translational applications.
View details for DOI 10.3390/gels9010019
View details for PubMedID 36661787
Topical vanadate improves tensile strength and alters collagen organization of excisional wounds in a mouse model.
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
Wound dehiscence, oftentimes a result of the poor tensile strength of early healing wounds, is a significant threat to the postoperative patient, potentially causing life-threatening complications. Vanadate, a protein tyrosine phosphatase inhibitor, has been shown to alter the organization of deposited collagen in healing wounds and significantly improve the tensile strength of incisional wounds in rats. In this study, we sought to explore the effects of locally administered vanadate on tensile strength and collagen organization in both the early and remodeling phases of excisional wound healing in a murine model. Wild-type mice underwent stented excisional wounding on their dorsal skin and were divided equally into three treatment conditions: vanadate injection, saline injection control, and an untreated control. Tensile strength testing, in vivo suction Cutometer analysis, gross wound measurements, and histologic analysis were performed during healing, immediately upon wound closure, and after four weeks of remodeling. We found that vanadate treatment significantly increased the tensile strength of wounds and their stiffness relative to control wounds, both immediately upon healing and into the remodeling phase. Histologic analysis revealed that these biomechanical changes were likely the result of increased collagen deposition and an altered collagen organization composed of thicker and distinctly organized collagen bundles. Given the risk that dehiscence poses to all operative patients, vanadate presents an interesting therapeutic avenue to improve the strength of post-operative wounds and unstable chronic wounds in order to reduce the risk of dehiscence.
View details for DOI 10.1111/wrr.13062
View details for PubMedID 36484112
Editorial for Special Issue on Machine Learning in Tissue Engineering.
Tissue engineering. Part A
View details for DOI 10.1089/ten.tea.2022.29038.editorial
View details for PubMedID 36399697
Adipose-Derived Stromal Cell-based Therapies for Radiation-Induced Fibrosis.
Advances in wound care
SIGNIFICANCE: Half of all cancer patients receive radiation therapy as a component of their treatment regimen, and the most common resulting complication is radiation-induced fibrosis of the skin and soft tissue. This thickening of the dermis paired with decreased vascularity results in functional limitations, aesthetic concerns, and poses unique challenges when considering surgical exploration or reconstruction. Existing therapeutic options for radiation-induced fibrosis of the skin are limited both in scope and efficacy. Cell-based therapies have emerged as a promising means of utilizing regenerative cell populations to improve both functional and aesthetic outcomes, and even as prophylaxis for radiation-induced fibrosis.RECENT ADVANCES: As one of the leading areas of cell-based therapy research, adipose-derived stromal cells (ADSCs) demonstrate significant therapeutic potential in the treatment of radiation-induced fibrosis (RIF). The introduction of the ADSC-augmented fat graft has shown clinical utility. Recent research dedicated to characterizing specific ADSC subpopulations points toward further granularity in understanding of the mechanisms driving the well-established clinical outcomes seen with fat grafting therapy.CRITICAL ISSUES: Various animal models of radiation-induced fibrosis demonstrated improved clinical outcomes following treatment with cell-based therapies, but the cellular and molecular basis underlying these effects remains poorly understood.FUTURE DIRECTIONS: Recent literature has focused on improving the efficacy of cell-based therapies, most notably through 1) augmentation of fat grafts with platelet-rich plasma and 2) the modification of expressed RNA through epitranscriptomics. For the latter, new and promising gene targets continue to be identified which have the potential to reverse the effects of fibrosis by increasing angiogenesis, decreasing inflammation, and promoting adipogenesis.
View details for DOI 10.1089/wound.2022.0103
View details for PubMedID 36345216
Machine Learning-Based Desmoplastic Signatures Predict Patient Outcomes in Pancreatic Ductal Adenocarcinoma
LIPPINCOTT WILLIAMS & WILKINS. 2022: S53-S54
View details for Web of Science ID 000867877000135
Inhibition of Yes-Associated Protein Promotes Skin Wound Regeneration in Large Animals
LIPPINCOTT WILLIAMS & WILKINS. 2022: S196
View details for DOI 10.1097/01.XCS.0000894508.92389.a2
View details for Web of Science ID 000867889300379
Adipocytes the Forgotten Culprit in Skin Fibrosis: Exploring the Mechanism of Fat Driven Skin Fibrosis
LIPPINCOTT WILLIAMS & WILKINS. 2022: S199
View details for DOI 10.1097/01.XCS.0000894536.38023.90
View details for Web of Science ID 000867889300387
Adipocyte Progenitor Cells Embedded in Collagen Gels Accelerate Bone Formation in a Murine Calvarial Critical Defect Model
LIPPINCOTT WILLIAMS & WILKINS. 2022: S198-S199
View details for DOI 10.1097/01.XCS.0000894532.90979.c9
View details for Web of Science ID 000867889300386
Transdermal Deferoxamine Improves Acute Wound Healing in Chronic Irradiated Skin in a Mouse Model
LIPPINCOTT WILLIAMS & WILKINS. 2022: S211-S212
View details for DOI 10.1097/01.XCS.0000894656.51739.b7
View details for Web of Science ID 000867889300416
Fibroblast Subpopulations Are Modified with Fat Grafting to Treat Radiation-Induced Fibrosis
LIPPINCOTT WILLIAMS & WILKINS. 2022: S202-S203
View details for DOI 10.1097/01.XCS.0000894568.35895.12
View details for Web of Science ID 000867889300395
Semantics Matter: Cheiloschisis Web-Based Information Differs from Cleft Lip
LIPPINCOTT WILLIAMS & WILKINS. 2022: S209
View details for DOI 10.1097/01.XCS.0000894628.90579.08
View details for Web of Science ID 000867889300410
Where There Is Fat There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation
LIPPINCOTT WILLIAMS & WILKINS. 2022: S59-S60
View details for DOI 10.1097/01.XCS.0000893384.03562.27
View details for Web of Science ID 000867889300098
Multi-Modal Analysis of Cell Populations and Architectural States Mediating the Progression and Resolution of Pulmonary Fibrosis
LIPPINCOTT WILLIAMS & WILKINS. 2022: S82
View details for Web of Science ID 000867877000204
Reversal of Senescence in Skin-derived Fibroblasts Using Exogenous Mechanical Stimulation
LIPPINCOTT WILLIAMS & WILKINS. 2022: S70
View details for Web of Science ID 000867877000176
Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.
Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.
View details for DOI 10.1016/j.ccell.2022.09.015
View details for PubMedID 36270275
Machine Learning in Tissue Engineering.
Tissue engineering. Part A
Machine learning (ML) and artificial intelligence have accelerated scientific discovery, augmented clinical practice, and deepened fundamental understanding of many biological phenomena. ML technologies have now been applied to diverse areas of tissue engineering research, including biomaterial design, scaffold fabrication, and cell/tissue modeling. Emerging ML-empowered strategies include machine-optimized polymer synthesis, predictive modeling of scaffold fabrication processes, complex analyses of structure-function relationships, and deep learning of spatialized cell phenotypes and tissue composition. The emergence of ML in tissue engineering, while relatively recent, has already enabled increasingly complex and multivariate analyses of the relationships between biological, chemical, and physical factors in driving tissue regenerative outcomes. This review highlights the novel methodologies, emerging strategies, and areas of potential growth within this rapidly evolving area of research.
View details for DOI 10.1089/ten.TEA.2022.0128
View details for PubMedID 35943870
Transdermal deferoxamine administration improves excisional wound healing in chronically irradiated murine skin.
Journal of translational medicine
2022; 20 (1): 274
BACKGROUND: Radiation-induced skin injury is a well-known risk factor for impaired wound healing. Over time, the deleterious effects of radiation on skin produce a fibrotic, hypovascular dermis poorly suited to wound healing. Despite increasing understanding of the underlying pathophysiology, therapeutic options remain elusive. Deferoxamine (DFO), an iron-chelating drug, has been shown in prior murine studies to ameliorate radiation-induced skin injury as well as improve wound healing outcomes in various pathologic conditions when administered transdermally. In this preclinical study, we evaluated the effects of deferoxamine on wound healing outcomes in chronically irradiated murine skin.METHODS: Wild-type mice received 30Gy of irradiation to their dorsal skin and were left to develop chronic fibrosis. Stented excisional wounds were created on their dorsal skin. Wound healing outcomes were compared across 4 experimental conditions: DFO patch treatment, vehicle-only patch treatment, untreated irradiated wound, and untreated nonirradiated wounds. Gross closure rate, wound perfusion, scar elasticity, histology, and nitric oxide assays were compared across the conditions.RESULTS: Relative to vehicle and untreated irradiated wounds, DFO accelerated wound closure and reduced the frequency of healing failure in irradiated wounds. DFO augmented wound perfusion throughout healing and upregulated angiogenesis to levels observed in nonirradiated wounds. Histology revealed DFO increased wound thickness, collagen density, and improved collagen fiber organization to more closely resemble nonirradiated wounds, likely contributing to the observed improved scar elasticity. Lastly, DFO upregulated inducible nitric oxide synthase and increased nitric oxide production in early healing wounds.CONCLUSION: Deferoxamine treatment presents a potential therapeutic avenue through which to target impaired wound healing in patients following radiotherapy.
View details for DOI 10.1186/s12967-022-03479-4
View details for PubMedID 35715816
Mechanical Stimulation Reverses Pro-Fibrotic Transcriptional States in Senescent Fibroblasts
WILEY. 2022: A33-A34
View details for Web of Science ID 000763583000075
Transdermal Deferoxamine Enhances Wound Healing In Chronically Irradiated Skin In Mice
WILEY. 2022: A29-A30
View details for Web of Science ID 000763583000068
Mechanical Stimulation Reverses Pro-Fibrotic Transcriptional States in Senescent Fibroblasts
WILEY. 2022: A14-A16
View details for Web of Science ID 000763583000039
Adipocytes Transition To Pro-Fibrotic Fibroblasts And Contribute To Muscle Fibrosis Following Nerve Injury
WILEY. 2022: A3-A4
View details for Web of Science ID 000763583000018