Publications

Jon-Paul Pepper, MD
Associate Professor of Otolaryngology — Head & Neck Surgery

Publications

  • Localized application of SAG21k-loaded fibrin hydrogels for targeted modulation of the hedgehog pathway in facial nerve injury. International journal of biological macromolecules He, L., Sato, J. E., Sundar, P., Azimi, T., Beachy, P. A., Bekale, L. A., Pepper, J. P. 2024: 131747

    Abstract

    Given the broad biological effects of the Hedgehog (Hh) pathway, there is potential clinical value in local application of Hh pathway modulators to restrict pathway activation of target tissues and avoid systemic pathway activation. One option to limit Hh pathway activation is using fibrin hydrogels to deliver pathway modulators directly to tissues of interest, bypassing systemic distribution of the drug. In this study, we loaded the potent Hh pathway agonist, SAG21k, into fibrin hydrogels. We describe the binding between fibrin and SAG21k and achieve sustained release of the drug in vitro. SAG21k-loaded fibrin hydrogels exhibit strong biological activity in vitro, using a pathway-specific reporter cell line. To test in vivo activity, we used a mouse model of facial nerve injury. Application of fibrin hydrogels is a common adjunct to surgical nerve repair, and the Hh pathway is known to play an important role in facial nerve injury and regeneration. Local application of the Hh pathway agonist SAG21k using a fibrin hydrogel applied to the site of facial nerve injury successfully activates the Hh pathway in treated nerve tissue. Importantly, this method appears to avoid systemic pathway activation when Hh-responsive organs are analyzed for transcriptional pathway activation. This method of local tissue Hh pathway agonist administration allows for effective pathway targeting surgically accessible tissues and may have translational value in situations where supranormal pathway activation is therapeutic.

    View details for DOI 10.1016/j.ijbiomac.2024.131747

    View details for PubMedID 38670196

  • Evidence Based Medicine for Facial Reanimation. Facial plastic surgery : FPS Kimura, K. S., Kfoury, P., Pepper, J. P. 2023

    Abstract

    This article provides a brief historical overview of the assessment instruments that have been developed to categorize the severity of disease in patients with facial palsy. Important advances in the quality of these instruments in discussed. The modern day instruments that are commonly required for evidenced-based patient assessment are then presented, with emphasis on the level of evidence of the studies that describe these instruments.

    View details for DOI 10.1055/a-2023-9051

    View details for PubMedID 36720255

  • Synkinesis and Communicative Participation. Facial plastic surgery & aesthetic medicine Okland, T. S., Willens, S. H., Pepper, J. 2022

    Abstract

    Background: Facial palsy (FP) impacts verbal and nonverbal communication, but the effect of synkinesis on communicative ability is unknown. Objective: Among patients with nonflaccid FP, or synkinesis, is there a correlation between disease-specific quality-of-life and communicative ability or dysfunction? Methods: Retrospective study of a series of adult patients with unilateral synkinesis. Subjects were evaluated using the Communicative Participation Item Bank (CPIB) Short Form, Facial Clinimetric Evaluation (FaCE) scale, and Synkinesis Assessment Questionnaire (SAQ). Associations between these scales were evaluated by computing Pearson correlation coefficients. Results: A total of 69 confirmed synkinesis patients were included. Synkinesis patient mean (standard deviation) CPIB score was 20.68 (±8.27; range of scale 0-30), indicative of communication restriction. A strong correlation was observed between total CPIB and FaCE scores (r=0.66), indicating patients with synkinesis who reported better facial function also reported greater communicative ability. There was a weak correlation between CPIB and SAQ scores (r=-0.27). Conclusion: Synkinesis is associated with significant deficits in communicative ability. Communication restrictions track strongly with the FaCE scale.

    View details for DOI 10.1089/fpsam.2022.0094

    View details for PubMedID 36260346

  • Facial Paralysis and Communicative Participation: The Importance of Facial Symmetry at Rest. The Annals of otology, rhinology, and laryngology Ayoub, N. F., Abdelwahab, M. n., Zhang, M. n., Ma, Y. n., Stranberg, S. n., Okland, T. S., Pepper, J. P. 2020: 3489420912446

    Abstract

    There is a paucity of research devoted to understanding the communication restrictions encountered by facial paralysis patients. We aim to explore the relationship between patient-reported restrictions in communicative participation and objective facial paralysis severity using validated scales of facial movement.We performed a pilot retrospective study using a consecutive series of adult patients with a diagnosis of unilateral facial paralysis. In addition to baseline demographics, subjects were evaluated using the Communicative Item Participation Bank Short Form (CPIB), Electronic Facial Assessment by Computer Evaluation (eFACE), and Sunnybrook Facial Grading System (SFGS).Twenty patients were included, 10 (50%) of whom were female with a mean age of 61 ± 13 years and mean duration of facial paralysis of 53 ± 82 months. The mean CPIB score was 14.6 ± 10.0 (range 0-29) and was comparable to scores of patients with conditions known to cause significant communicative disability. The mean eFACE scores were 67.4 ± 29.2, 44.2 ± 30.1, and 73.8 ± 30.0 for the static, dynamic, and synkinesis domains, respectively, with a composite smile score of 58.5 ± 16.9. After adjusting for age, gender, and duration of facial paralysis, significant moderate correlations were observed between the CPIB and the static eFACE domain (r = -0.51, P = .03) and smile composite score (r = 0.48, P = 0.0049), in addition to between the CPIB and SFGS synkinesis domain (r = 0.48, P = 0.04).Patients with unilateral facial paralysis experience significant limitations in communicative participation. These restrictions demonstrate moderate to strong correlations with objective assessments of facial paralysis and quality of life measures. Communicative participation may be a helpful means of tracking response to treatment.IV.

    View details for DOI 10.1177/0003489420912446

    View details for PubMedID 32192355

  • Dual Nerve Transfer for Facial Reanimation JAMA FACIAL PLASTIC SURGERY Pepper, J. 2019; 21 (3): 260–61
  • Speech and Communicative Participation in Patients With Facial Paralysis. JAMA otolaryngology-- head & neck surgery Kim, J. H., Fisher, L. M., Reder, L., Hapner, E. R., Pepper, J. 2018; 144 (8): 686–93

    Abstract

    Importance: Problems with speech in patients with facial paralysis are frequently noted by both clinicians and the patients themselves, but limited research exists describing how facial paralysis affects verbal communication.Objective: To assess the influence of facial paralysis on communicative participation.Design, Setting, and Participants: A nationwide online survey of 160 adults with unilateral facial paralysis was conducted from March 1 to June 1, 2017. To assess communicative participation, respondents completed the Communicative Participation Item Bank (CPIB) Short Form questionnaire and the Facial Clinimetric Evaluation (FaCE) Scale.Main Outcomes and Measures: The CPIB Short Form and the correlation between the CPIB Short Form and FaCE Scale. In the CPIB, the level of interference in communication is rated on a 4-point Likert scale (where not at all=3, a little=2, quite a bit=1, and very much=0). Total scores for the 10 items range from 0 (worst) to 30 (best). The FaCE Scale is a 15-item instrument that produces an overall score ranging from 0 (worst) to 100 (best), with higher scores representing better function and higher quality of life.Results: Of the 160 respondents, 145 (90.6%) were women and 15 were men (mean [SD] age, 45.1 [12.6] years). Most respondents reported having facial paralysis for more than 3 years. Causes of facial paralysis included Bell palsy (86 [53.8%]), tumor (41 [25.6%]), and other causes (33 [20.6%]), including infection, trauma, congenital defects, and surgical complications. The mean (SD) score on the CPIB Short Form was 0.16 (0.88) logits (range, -2.58 to 2.10 logits). The mean (SD) score of the FaCE Scale was 40.92 (16.05) (range, 0-83.3). Significant correlations were observed between the CPIB Short Form and overall FaCE Scale scores, as well as the Social Function, Oral Function, Facial Comfort, and Eye Comfort subdomains of the FaCE Scale, but not with the Facial Movement subdomain.Conclusions and Relevance: Patients with facial paralysis in this study sample reported restrictions in communicative participation that were comparable with restrictions experienced by patients with other known communicative disorders, such as laryngectomy and head and neck cancer. We believe that communicative participation represents a unique domain of dysfunction and can help quantify the outcome of facial paralysis and provide an additional frame of reference when assessing treatment outcomes.

    View details for PubMedID 29955841

  • The role of Hedgehog-responsive fibroblasts in facial nerve regeneration EXPERIMENTAL NEUROLOGY Dogaru, G., Juneja, S. C., Shokrani, A., Hui, R. Y., Chai, Y., Pepper, J. 2018; 303: 72–79

    Abstract

    Facial nerve paralysis is a significant cause of morbidity, affecting facial appearance, emotional expression, speech, oral competence, and vision. A more complete understanding of the complex cellular events required for successful nerve regeneration may reveal new therapeutic targets. The role of fibroblasts in regeneration, and the process by which the nerve reforms its three-dimensional structure after a transection injury, are not fully understood. The Hedgehog signaling pathway has been shown to mediate nerve sheath formation during development. We therefore sought to characterize the role of Hedgehog-responsive cells following transection of the facial nerve.Two transgenic mouse lines with reporters for the downstream effector of Hedgehog signaling, Gli1, were used. The animals underwent a unilateral facial nerve transection injury, and the contralateral side served as a control. Facial nerves were analyzed via immunohistochemistry and immunofluorescence at predetermined time points as the facial nerve regenerated after the transection injury.There was a statistically significant increase in Gli1+ cells both at the site of injury and within the distal nerve segment over time. Gli1+ cells are fibroblasts within the nerve and appear to contribute to the reformation of the nerve sheath after injury.These findings describe a key signaling pathway by which fibroblasts participate in motor nerve regeneration. Fibroblasts that reside within the nerve respond to injury and may represent a novel therapeutic target in the context of facial nerve regeneration after transection injury.

    View details for PubMedID 29337143

  • Human Induced Pluripotent Stem Cell-Derived Motor Neuron Transplant for Neuromuscular Atrophy in a Mouse Model of Sciatic Nerve Injury. JAMA facial plastic surgery Pepper, J., Wang, T. V., Hennes, V., Sun, S. Y., Ichida, J. K. 2017; 19 (3): 197-205

    Abstract

    Human motor neurons may be reliably derived from induced pluripotent stem cells (iPSCs). In vivo transplant studies of human iPSCs and their cellular derivatives are essential to gauging their clinical utility.To determine whether human iPSC-derived motor neurons can engraft in an immunodeficient mouse model of sciatic nerve injury.This nonblinded interventional study with negative controls was performed at a biomedical research institute using an immunodeficient, transgenic mouse model. Induced pluripotent stem cell-derived motor neurons were cultured and differentiated. Cells were transplanted into 32 immunodeficient mice with sciatic nerve injury aged 6 to 15 weeks. Tissue analysis was performed at predetermined points after the mice were killed humanely. Animal experiments were performed from February 24, 2015, to May 2, 2016, and data were analyzed from April 7, 2015, to May 27, 2016.Human iPSCs were used to derive motor neurons in vitro before transplant.Evidence of engraftment based on immunohistochemical analysis (primary outcome measure); evidence of neurite outgrowth and neuromuscular junction formation (secondary outcome measure); therapeutic effect based on wet muscle mass preservation and/or electrophysiological evidence of nerve and muscle function (exploratory end point).In 13 of the 32 mice undergoing the experiment, human iPSC-derived motor neurons successfully engrafted and extended neurites to target denervated muscle. Human iPSC-derived motor neurons reduced denervation-induced muscular atrophy (mean [SD] muscle mass preservation, 54.2% [4.0%]) compared with negative controls (mean [SD] muscle mass preservation, 33.4% [2.3%]) (P = .04). No electrophysiological evidence of muscle recovery was found.Human iPSC-derived motor neurons may have future use in the treatment of peripheral motor nerve injury, including facial paralysis.NA.

    View details for DOI 10.1001/jamafacial.2016.1544

    View details for PubMedID 27978547