establishment-robust-reproducible-model-radiation-induced-skin-muscle

Establishment of a Robust and Reproducible Model of Radiation-Induced Skin and Muscle Fibrosis

Radiation-induced skin fibrosis (RISF) can result from a plethora of scenarios including cancer therapy, accidental exposure, or acts of terrorism. ...

University of Pittsburgh

Injuries to peripheral nerves cause distal muscle atrophy. The effects of adipose-derived stem cell (ASC) injections into a muscle after injury were examined.

Adipose-derived stem cells delay muscle atrophy after peripheral nerve injury in the rodent model.

Adipose tissue reaches cellular stasis after puberty, leaving adipocytes unable to significantly expand or renew under normal physiologic conditions. This is problematic in progressive lipodystrophies, in instances of scarring, and in soft-tissue damage resulting from lumpectomy and traumatic deformities, because adipose tissue will not self-renew once damaged. This yields significant clinical necessity for an off-the-shelf de novo soft-tissue replacement mechanism.

Injectable Allograft Adipose Matrix Supports Adipogenic Tissue Remodeling in the Nude Mouse and Human.

Severe peripheral nerve injuries have devastating consequences on the quality of life in affected patients, and they represent a significant unmet medical need. Destruction of nerve fibers results in denervation of targeted muscles, which, subsequently, undergo progressive atrophy and loss of function. Timely restoration of neural innervation to muscle fibers is crucial to the preservation of muscle homeostasis and function. The goal of this study was to evaluate the impact of addition of adipose stem cells (ASCs) to polycaprolactone (PCL) nerve conduit guides on peripheral nerve repair and functional muscle recovery in the setting of a critical size nerve defect. To this end, peripheral nerve injury was created by surgically ablating 6 mm of the common peroneal nerve in a rat model. A PCL nerve guide, filled with ASCs and/or poloxamer hydrogel, was sutured to the nerve ends. Negative and positive controls included nerve ablation only (no repair), and reversed polarity autograft nerve implant, respectively. Tibialis anterior (TA) muscle function was assessed at 4, 8, and 12 weeks postinjury, and nerve and muscle tissue was retrieved at the 12-week terminal time point. Inclusion of ASCs in the PCL nerve guide elicited statistically significant time-dependent increases in functional recovery (contraction) after denervation; ∼25% higher than observed in acellular (poloxamer-filled) implants and indistinguishable from autograft implants, respectively, at 12 weeks postinjury ( < 0.05,  = 7-8 in each group). Analysis of single muscle fiber cross-sectional area (CSA) revealed that ASC-based treatment of nerve injury provided a better recapitulation of the overall distribution of muscle fiber CSAs observed in the contralateral TA muscle of uninjured limbs. In addition, the presence of ASCs was associated with improved features of re-innervation distal to the defect, with respect to neurofilament and S100 (Schwann cell marker) expression. In conclusion, these initial studies indicate significant benefits of inclusion of ASCs to the rate and magnitude of both peripheral nerve regeneration and functional recovery of muscle contraction, to levels equivalent to autograft implantation. These findings have important implications to improved nerve repair, and they provide input for future work directed to restoration of nerve and muscle function after polytraumatic injury. Impact Statement This works explores the application of adipose stem cells (ASCs) for peripheral nerve regeneration in a rat model. Herein, we demonstrate that the addition of ASCs in poloxamer-filled PCL nerve guide conduits impacts nerve regeneration and recovery of muscle function, to levels equivalent to autograft implantation, which is considered to be the current gold standard treatment. This study builds on the importance of a timely restoration of innervation to muscle fibers for preservation of muscle homeostasis, and it will provide input for future work aiming at restoring nerve and muscle function after polytraumatic injury.

Adipose Stem Cells Enhance Nerve Regeneration and Muscle Function in a Peroneal Nerve Ablation Model.

Plastic surgery trainees who wish to start a family face challenges. This is the first study to collect data directly from residents and fellows to understand issues surrounding childbearing and to propose solutions.

The Impact of Plastic Surgery Training on Family Planning and Prenatal Health.

Tissue decellularization for generating extracellular matrices has become a staple of regenerative medicine in the recent decades, extending from the research setting to clinical usage. Although methods and protocols for tissue decellularization are abundant throughout the literature, they can be time intensive and typically require specific overhead in terms of equipment. To reduce these barriers to entry, a functional and reproducible prototype of a tissue infusion/perfusion device (TIPD) has been designed and fabricated using three-dimensional printed parts in conjunction with commercially available components. This TIPD forms a system composed of two peristaltic pumps, two 3-way valves, and a chamber in which tissue is contained, and is controlled by user-customizable software. To increase repeatability among decellularization protocols, an automation function has been integrated into the software, which is able to specify fluid flow rates and define specific valve locations enabling selection of solutions to be introduced into a scaffold over the course of a decellularization process. The prototype has been tested for proof of concept through infusion and perfusion decellularization of skeletal muscle and intact kidneys, respectively, and has shown successful removal of cellular content while maintaining an intact ultrastructure. In an effort to increase the reproducibility of experimental designs and to promote an open source hardware initiative in the field of tissue engineering, a novel device was conceptualized and prototyped with printable part files made available for its fabrication in tandem with instructions for assembly. Impact Statement Repeatable methods for decellularization are essential for achieving consistent substrates between batches, laboratories, and facilities. To meet this end, an automatable tissue infusion/perfusion device composed of three-dimensional printed parts and commercially available components has been prototyped and tested. Materials and instructions for its assembly have been made available in an effort to reduce variability among equipment as well as to provide a platform on which to iterate open-source hardware in tissue engineering.

Design and Fabrication of an Automatable, 3D Printed Perfusion Device for Tissue Infusion and Perfusion Engineering.

Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line-derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, and -ratio. PCL/GDNF group exhibited a statistically greater average area occupied by individual Schwann cells at the distal nerve (11.60 ± 33.01 μm) compared to autograft (4.62 ± 3.99 μm) and PCL/Empty (4.52 ± 5.16 μm) treatment groups. This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit.

Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates.

Biomaterials derived from human adipose extracellular matrix have shown promise in vitro and in animal studies as an off-the-shelf adipogenic matrix for sustained volume replacement. Herein, we report the results of a randomized prospective study conducted with allograft adipose matrix (AAM) grafted into the pannus of presurgical abdominoplasty patients 3 or 6 months before scheduled surgery. This is the first report of a longitudinal histologic analysis of AAM in clinical use.

Clinical Evaluation of an Off-the-Shelf Allogeneic Adipose Matrix for Soft Tissue Reconstruction.

Throughout the coronavirus disease 2019 pandemic, many emergency departments have been using passive protective enclosures ("intubation boxes") during intubation. The effectiveness of these enclosures remains uncertain. We sought to quantify their ability to contain aerosols using industry standard test protocols.

Improved Testing and Design of Intubation Boxes During the COVID-19 Pandemic.

Gender bias and sexual misconduct continue to pervade medicine. The authors hypothesize that gender bias and sexual misconduct disproportionately and negatively affect female plastic surgery trainees.

A Report of Gender Bias and Sexual Harassment in Current Plastic Surgery Training: A National Survey.

Peripheral nerve injury and the associated muscle atrophy has an estimated annual healthcare burden of $150 billion dollars in the United States. When considering the total annual health-related spending of $3.5 trillion, these pathologies alone occupy about 4.3%. The prevalence of these ailments is rooted, at least in part, in the lack of specific preventative therapies that can be administered to muscle while it remains in the denervated state. To address this, skeletal muscle-derived ECM (skECM) was injected directly in denervated muscle with postoperative analysis performed at 20 weeks, including gait analysis, force production, cytokine quantification, and histological analysis. skECM was shown to be superior against non-injected muscle controls showing no difference in contraction force to uninjured muscle at 20 weeks. Cytokines IL-1β, IL-18, and IFNγ appeared to mediate regeneration with statistical regression implicating these cytokines as strong predictors of muscle contraction, showing significant linear correlation.

Article	Year
Adipose-derived stem cells delay muscle atrophy after peripheral nerve injury in the rodent model. Muscle & nerve\| PubMed ID: 30681163	2019
Injectable Allograft Adipose Matrix Supports Adipogenic Tissue Remodeling in the Nude Mouse and Human. Plastic and reconstructive surgery\| PubMed ID: 30688888	2019
Adipose Stem Cells Enhance Nerve Regeneration and Muscle Function in a Peroneal Nerve Ablation Model. Tissue engineering. Part A\| PubMed ID: 30760135	2021
The Impact of Plastic Surgery Training on Family Planning and Prenatal Health. Plastic and reconstructive surgery\| PubMed ID: 31688771	2019
Design and Fabrication of an Automatable, 3D Printed Perfusion Device for Tissue Infusion and Perfusion Engineering. Tissue engineering. Part A\| PubMed ID: 31746678	2020
Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates. Science translational medicine\| PubMed ID: 31969488	2020
Clinical Evaluation of an Off-the-Shelf Allogeneic Adipose Matrix for Soft Tissue Reconstruction. Plastic and reconstructive surgery. Global open\| PubMed ID: 32095393	2020
Improved Testing and Design of Intubation Boxes During the COVID-19 Pandemic. Annals of emergency medicine\| PubMed ID: 32893040	2021
A Report of Gender Bias and Sexual Harassment in Current Plastic Surgery Training: A National Survey. Plastic and reconstructive surgery\| PubMed ID: 34019520	2021
Intramuscular injection of skeletal muscle derived extracellular matrix mitigates denervation atrophy after sciatic nerve transection. Journal of tissue engineering\| PubMed ID: 34567507	2021

Benjamin K. Schilling

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