Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Mechanization and Assessment of Regenerative Therapies for Peripheral Nerve Injury and the Associated Muscle Atrophy

Schilling, Benjamin (2021) Mechanization and Assessment of Regenerative Therapies for Peripheral Nerve Injury and the Associated Muscle Atrophy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Download (15MB) | Preview


Peripheral nerve injury (PNI) not only results in nerve dysfunction but also induces adverse changes in the muscular microenvironment, resulting in muscle atrophy (MA). The time needed for nerve regeneration results in downstream, distal musculature denervation. Muscle denervation prompts significant stiffening, fiber shrinkage, and decrease or loss in force generation. Additionally, the probability of restoring muscle to the preinjury state is proportional to the time of nerve healing, where longer healing time lessens the likelihood that the muscle will regain function, even if the nerve itself is regenerated. While surgical treatment of PNI includes an assortment of interventions, no specific interventions are indicated for MA at the time of PNI. Rather, physical rehabilitation after nerve repair is prescribed, but is presupposed by partial muscle reinnervation. The lack of specific interventions led to the central hypothesis that MA occurring after PNI can be minimized by administering an intramuscular therapy directly into a denervated muscle, altering fibrogenesis, lipogenesis, and inflammation.
In the sciatic nerve injury model, atrophy of distal muscle, including the gastrocnemius, occurred. Both cellular and acellular therapies were administered directly into gastrocnemii, being adipose-derived stem cells (ASCs), a preparation of emulsified adipose tissue (“Nanofat”), and a skeletal muscle-derived extracellular matrix (skECM). Additionally, in select conditions a polycaprolactone nerve wrap was applied at the nerve injury site to assess cotreatment of muscle and nerve. Two automated devices were created to produce neuromuscular therapies: An automated dip coating device was used fabricate nerve wraps and an automated perfusion machine was used to produce skECM. Studies were conducted with postoperative analyses performed at 6, 9, 12, and 20 weeks, which included gait assessment, force production, cytokine quantification, and histological analysis. Intramuscular therapies, particularly skECM, were shown to be beneficial against non-injected muscle controls across all time points and showed no significant difference to uninjured muscle at 20 weeks. Cytokines interleukin (IL)-1beta, IL-18, and vascular endothelial growth factor (VEGF) appeared to mediate regeneration throughout. Statistical regression implicated IL-1beta, IL-18, and their interacting effects as strong predictors of muscle contraction. These investigations implicate intramuscular treatment as a worthwhile co-therapy for the PNI patent population.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Schilling, Benjaminbes111@pitt.edubes1110000-0002-5509-0803
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMarra, Kacey G.marrak@upmc.edukgm50000-0002-8437-4864
Committee MemberMoyer, Brian E.bmoyer@pitt.edubmoyer
Committee MemberPhillippi, Julie A.phillippija@upmc.edujap1030000-0002-9879-2039
Committee MemberRubin, J. Peterrubipj@UPMC.EDUjpr50000-0003-2040-6051
Committee MemberWagner, William R.wagnerwr@upmc.eduwagnerwr
Date: 18 June 2021
Date Type: Publication
Defense Date: 8 March 2021
Approval Date: 18 June 2021
Submission Date: 9 March 2021
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 305
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Muscle atrophy; denervation; nerve injury; extracellular matrix; Nanofat; perfusion bioreactor; inflammation; interleukin
Date Deposited: 18 Jun 2022 05:00
Last Modified: 18 Jun 2022 05:15


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item