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Title: Developing a Synthetic Hydrogel for Breast Tissue Engineering
As part of the PI's outreach, a course-based undergraduate research experience engaged undergraduate women in research from examining the literature to identify a gap, formulating a research hypothesis, designing experiments to test the hypothesis, analyzing the data, writing and submitting an abstract and presenting the research to the scientific community. This project was as follows: Current clinical approaches to repair breast damage from cancer resection, injury, or deformity focus on synthetic implants or autologous muscle grafts. While there are drawbacks and benefits to each, neither restore the function lost should the woman desire to nurse children. Tissue engineering methods have the potential to restore breast tissue volume and function that circumvent the reconstructive limitations of contemporary surgical procedures. There is a large body of research on breast tissue engineering; however, much of the research focuses on restoring breast volume rather than breast function and seek to replace the missing tissue with fat or muscle.​ Here, we aim to develop a scaffold capable of supporting both breast adipose and glandular tissue (the main components of breast tissue) towards restoring both form and function to the breast.  more » « less
Award ID(s):
1752079
NSF-PAR ID:
10139168
Author(s) / Creator(s):
; ; ;
Date Published:
Journal Name:
Biomedical Engineering Society
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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  1. Abstract

    Skeletal muscle's isometric contractile properties are one of the classic structure–function relationships in all of biology allowing for extrapolation of single fibre mechanical properties to whole muscle properties based on the muscle's optimal fibre length and physiological cross‐sectional area (PCSA). However, this relationship has only been validated in small animals and then extrapolated to human muscles, which are much larger in terms of length and PCSA. The present study aimed to measure directly thein situproperties and function of the human gracilis muscle to validate this relationship. We leveraged a unique surgical technique in which a human gracilis muscle is transferred from the thigh to the arm, restoring elbow flexion after brachial plexus injury. During this surgery, we directly measured subject specific gracilis muscle force–length relationshipin situand propertiesex vivo. Each subject's optimal fibre length was calculated from their muscle's length‐tension properties. Each subject's PCSA was calculated from their muscle volume and optimal fibre length. From these experimental data, we established a human muscle fibre‐specific tension of 171 kPa. We also determined that average gracilis optimal fibre length is 12.9 cm. Using this subject‐specific fibre length, we observed an excellent fit between experimental and theorical active length‐tension curves. However, these fibre lengths were about half of the previously reported optimal fascicle lengths of 23 cm. Thus, the long gracilis muscle appears to be composed of relatively short fibres acting in parallel that may not have been appreciated based on traditional anatomical methods.image

    Key points

    Skeletal muscle's isometric contractile properties represent one of the classic structure–function relationships in all of biology and allow scaling single fibre mechanical properties to whole muscle properties based on the muscle's architecture.

    This physiological relationship has only been validated in small animals but is often extrapolated to human muscles, which are orders of magnitude larger.

    We leverage a unique surgical technique in which a human gracilis muscle is transplanted from the thigh to the arm to restore elbow flexion after brachial plexus injury, aiming to directly measure muscles propertiesin situand test directly the architectural scaling predictions.

    Using these direct measurements, we establish human muscle fibre‐specific tension of ∼170 kPa.

    Furthermore, we show that the gracilis muscle actually functions as a muscle with relatively short fibres acting in parallelvs. long fibres as previously assumed based on traditional anatomical models.

     
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  2. Obeid, Iyad ; Picone, Joseph ; Selesnick, Ivan (Ed.)
    The Neural Engineering Data Consortium (NEDC) is developing a large open source database of high-resolution digital pathology images known as the Temple University Digital Pathology Corpus (TUDP) [1]. Our long-term goal is to release one million images. We expect to release the first 100,000 image corpus by December 2020. The data is being acquired at the Department of Pathology at Temple University Hospital (TUH) using a Leica Biosystems Aperio AT2 scanner [2] and consists entirely of clinical pathology images. More information about the data and the project can be found in Shawki et al. [3]. We currently have a National Science Foundation (NSF) planning grant [4] to explore how best the community can leverage this resource. One goal of this poster presentation is to stimulate community-wide discussions about this project and determine how this valuable resource can best meet the needs of the public. The computing infrastructure required to support this database is extensive [5] and includes two HIPAA-secure computer networks, dual petabyte file servers, and Aperio’s eSlide Manager (eSM) software [6]. We currently have digitized over 50,000 slides from 2,846 patients and 2,942 clinical cases. There is an average of 12.4 slides per patient and 10.5 slides per case with one report per case. The data is organized by tissue type as shown below: Filenames: tudp/v1.0.0/svs/gastro/000001/00123456/2015_03_05/0s15_12345/0s15_12345_0a001_00123456_lvl0001_s000.svs tudp/v1.0.0/svs/gastro/000001/00123456/2015_03_05/0s15_12345/0s15_12345_00123456.docx Explanation: tudp: root directory of the corpus v1.0.0: version number of the release svs: the image data type gastro: the type of tissue 000001: six-digit sequence number used to control directory complexity 00123456: 8-digit patient MRN 2015_03_05: the date the specimen was captured 0s15_12345: the clinical case name 0s15_12345_0a001_00123456_lvl0001_s000.svs: the actual image filename consisting of a repeat of the case name, a site code (e.g., 0a001), the type and depth of the cut (e.g., lvl0001) and a token number (e.g., s000) 0s15_12345_00123456.docx: the filename for the corresponding case report We currently recognize fifteen tissue types in the first installment of the corpus. The raw image data is stored in Aperio’s “.svs” format, which is a multi-layered compressed JPEG format [3,7]. Pathology reports containing a summary of how a pathologist interpreted the slide are also provided in a flat text file format. A more complete summary of the demographics of this pilot corpus will be presented at the conference. Another goal of this poster presentation is to share our experiences with the larger community since many of these details have not been adequately documented in scientific publications. There are quite a few obstacles in collecting this data that have slowed down the process and need to be discussed publicly. Our backlog of slides dates back to 1997, meaning there are a lot that need to be sifted through and discarded for peeling or cracking. Additionally, during scanning a slide can get stuck, stalling a scan session for hours, resulting in a significant loss of productivity. Over the past two years, we have accumulated significant experience with how to scan a diverse inventory of slides using the Aperio AT2 high-volume scanner. We have been working closely with the vendor to resolve many problems associated with the use of this scanner for research purposes. This scanning project began in January of 2018 when the scanner was first installed. The scanning process was slow at first since there was a learning curve with how the scanner worked and how to obtain samples from the hospital. From its start date until May of 2019 ~20,000 slides we scanned. In the past 6 months from May to November we have tripled that number and how hold ~60,000 slides in our database. This dramatic increase in productivity was due to additional undergraduate staff members and an emphasis on efficient workflow. The Aperio AT2 scans 400 slides a day, requiring at least eight hours of scan time. The efficiency of these scans can vary greatly. When our team first started, approximately 5% of slides failed the scanning process due to focal point errors. We have been able to reduce that to 1% through a variety of means: (1) best practices regarding daily and monthly recalibrations, (2) tweaking the software such as the tissue finder parameter settings, and (3) experience with how to clean and prep slides so they scan properly. Nevertheless, this is not a completely automated process, making it very difficult to reach our production targets. With a staff of three undergraduate workers spending a total of 30 hours per week, we find it difficult to scan more than 2,000 slides per week using a single scanner (400 slides per night x 5 nights per week). The main limitation in achieving this level of production is the lack of a completely automated scanning process, it takes a couple of hours to sort, clean and load slides. 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Our near-term goal for the TUDP Corpus is to release 100,000 slides by December 2020. We hope to continue data collection over the next decade until we reach one million slides. We are creating two pilot corpora using the first 50,000 slides we have collected. The first corpus consists of 500 slides with a marker stain and another 500 without it. This set was designed to let people debug their basic deep learning processing flow on these high-resolution images. We discuss our preliminary experiments on this corpus and the challenges in processing these high-resolution images using deep learning in [3]. We are able to achieve a mean sensitivity of 99.0% for slides with pen marks, and 98.9% for slides without marks, using a multistage deep learning algorithm. While this dataset was very useful in initial debugging, we are in the midst of creating a new, more challenging pilot corpus using actual tissue samples annotated by experts. The task will be to detect ductal carcinoma (DCIS) or invasive breast cancer tissue. There will be approximately 1,000 images per class in this corpus. Based on the number of features annotated, we can train on a two class problem of DCIS or benign, or increase the difficulty by increasing the classes to include DCIS, benign, stroma, pink tissue, non-neoplastic etc. Those interested in the corpus or in participating in community-wide discussions should join our listserv, nedc_tuh_dpath@googlegroups.com, to be kept informed of the latest developments in this project. You can learn more from our project website: https://www.isip.piconepress.com/projects/nsf_dpath. 
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  3. Abstract

    A heart attack results in the permanent loss of heart muscle and can lead to heart disease, which kills more than 7 million people worldwide each year. To date, outside of heart transplantation, current clinical treatments cannot regenerate lost heart muscle or restore full function to the damaged heart. There is a critical need to create engineered heart tissues with structural complexity and functional capacity needed to replace damaged heart muscle. The inextricable link between structure and function suggests that hydrogel composites hold tremendous promise as a biomaterial‐guided strategy to advance heart muscle tissue engineering. Such composites provide biophysical cues and functionality as a provisional extracellular matrix that hydrogels cannot on their own. This review describes the latest advances in the characterization of these biomaterial systems and using them for heart muscle tissue engineering. The review integrates results across the field to provide new insights on critical features within hydrogel composites and perspectives on the next steps to harnessing these promising biomaterials to faithfully reproduce the complex structure and function of native heart muscle.

     
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  4. Background:

    Thigh muscle weakness after anterior cruciate ligament reconstruction (ACLR) can persist after returning to activity. While resistance training can improve muscle function, “nonfunctional” training methods are not optimal for inducing transfer of benefits to activities such as walking. Here, we tested the feasibility of a novel functional resistance training (FRT) approach to restore strength and function in an individual with ACLR.

    Hypothesis:

    FRT would improve knee strength and function after ACLR.

    Study Design:

    Case report.

    Level of Evidence:

    Level 5.

    Methods:

    A 15-year-old male patient volunteered for an 8-week intervention where he performed 30 minutes of treadmill walking, 3 times per week, while wearing a custom-designed knee brace that provided resistance to the thigh muscles of his ACLR leg. Thigh strength, gait mechanics, and corticospinal and spinal excitability were assessed before and immediately after the 8-week intervention. Voluntary muscle activation was evaluated immediately after the intervention.

    Results:

    Knee extensor and flexor strength increased in the ACLR leg from pre- to posttraining (130 to 225 N·m [+74%] and 44 to 88 N·m [+99%], respectively) and increases in between-limb extensor and flexor strength symmetry (45% to 92% [+74%] and 47% to 72% [+65%], respectively) were also noted. After the intervention, voluntary muscle activation in the ACLR leg was 72%, compared with the non-ACLR leg at 75%. Knee angle and moment during late stance phase decreased (ie, improved) in the ACLR leg and appeared more similar to the non-ACLR leg after FRT training (18° to 14° [−23.4] and 0.07 to −0.02 N·m·kg−1·m−1[−122.8%], respectively). Corticospinal and spinal excitability in the ACLR leg decreased (3511 to 2511 [−28.5%] and 0.42 to 0.24 [−43.7%], respectively) from pre- to posttraining.

    Conclusion:

    A full 8 weeks of FRT that targeted both quadriceps and hamstring muscles lead to improvements in strength and gait, suggesting that FRT may constitute a promising and practical alternative to traditional methods of resistance training.

    Clinical Relevance:

    FRT may serve as a viable approach to improve knee strength and function after ACL reconstruction.

     
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  5. Optical coherence tomography (OCT) is a rapid non‐invasive imaging technique that has shown high sensitivity for intra‐operative surgical margin assessment in human breast cancer clinical trials. This promising technology has not been evaluated in veterinary medicine. The objective of this study was to correlate normal and abnormal histological features with OCT images for surgical margins from excised canine soft tissue sarcoma (STS) and to establish image evaluation criteria for identifying positive surgical margins. Fourteen client‐owned dogs underwent surgical resection of a STS and OCT imaging of 2 to 4 areas of interest on the resected specimen were performed. Following imaging these areas were marked with surgical ink and trimmed for histopathology evaluation. Results showed that different tissue types had distinct characteristic appearances on OCT imaging. Adipose tissue exhibited a relatively low scattering and a honey‐comb texture pattern. Skeletal muscle and sarcoma tissue were both dense and highly scattering. While sarcoma tissue was highly scattering, it did not have organized recognizable structure in contrast to muscle which showed clear fibre alignment patterns. In this investigation, we showed different tissue types had different and characteristic scattering and image texture appearances on OCT, which closely correlate with low‐power histology images. Given the differentiation between tissue types the results support that OCT could be used to identify positive surgical margins immediately following resection of STS. Further research is needed to assess the diagnostic accuracy of this method for surgical margin assessment.

     
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