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URMC / Labs / Loiselle Lab

Loiselle Lab

Alayna E. Loiselle, Ph.D.

Post-doctoral training 2009-2013,
Penn State College of Medicine

Ph.D. 2009, University of Rochester
School of Medicine and Dentistry

Assistant Professor of Orthopaedics

Primary Appointment: Department of Orthopaedics

Center Affiliation: Center for Musculoskeletal Research

Graduate Program Affiliations: Cellular Basis of Disease and Genetics, Development, and Stem Cells

Research Overview

Picrosirius Sagittal Foot

Tendon Healing

 

 

 

 



The overarching goal of our research program is to identify novel strategies to improve post-operative tendon healing by modulating the pathological fibrotic healing response and promoting a more regenerative healing program. This fibrotic scar tissue results in impaired tendon function due to extracellular matrix (ECM) disorganization and inferior mechanical properties, relative to healthy tendon. Currently, there are no biological therapies to improve tendon repair outcomes. To facilitate identification of therapeutics we have developed a mouse model of tendon healing that heals with abundant scar formation and restricted tendon range of motion (ROM) and insufficient restoration of mechanical properties.  Use of this model facilitates the development of the research programs outlined below.

Research Programs

Tendon Cell Lineage Tracing
Tendon Cell Lineage

Our understanding of the mechanisms that govern fibrotic tendon healing remains limited, and this gap in knowledge has resulted in a paucity of therapeutic targets to improve clinical outcomes. We propose that identifying and delineating the functions of different cell populations (both intrinsic and extrinsic to the tendon) will facilitate more rationale identification of potential therapeutics.

 

 

Diabetic Tendon Healing

Type II Diabetes Mellitus (T2DM) further complicates an already challenging healing paradigm after surgical tendon repair. Non-diabetic tendons heal via a bridging scar tissue response rather than regeneration of native tendon structure. This scar tissue is composed of disorganized ECM that is mechanically inferior to native tendon, raising the risk of re-injury or rupture. The fibrotic scar tissue response is amplified by a greater degree of collagen ECM disorganization in T2DM tendons. Indeed, we and others have demonstrated significant decrements in mechanical properties during healing in diabetic tendons, and we have shown that ROM is also significantly impaired in T2DM tendon repairs. However, it is not known why T2DM tendons have such poor healing outcomes. Recent work from our Lineage Tracing program has identified S100a4 as a critical driver of fibrotic tendon healing, and we are investigated over-active S100a4 as a potential mechanism driving further impairments in diabetic tendon healing.

Non-invasive Quantitative Assessment of Tendon Healing Using Ultrasound and Machine Learning

Ultrasound

Following surgical repair, tendon injuries heal with function-limiting and mechanically insufficient scar tissue. Despite attempts using a variety of biological and tissue engineering approaches, there is currently no consensus therapy to improve outcomes after tendon injury. An insufficient understanding of the underlying mechanisms that contribute to scar-mediated tendon healing is a major impediment to the development of successful therapies. To address this limitation we developed a murine model of tendon injury and repair that recapitulates many clinical aspects of healing including abundant scar tissue formation and impaired restoration of mechanical properties. However, progress in this field is limited by the absence of cost-effective longitudinal outcome measures of tendon healing. For example, restoration of tendon gliding function, mechanical properties and tissue morphology are assessed by end-point analyses, which requires sacrificing the mice, and destructive testing of the tissue. Thus, current approaches are expensive, time-consuming and do not allow longitudinal evaluation or concomitant assessment of function and tissue morphology in the same specimen. Therefore, our objective is to develop longitudinal, non-invasive metrics of tendon healing by combining ultrasound (US) elasticity imaging and novel image registration methods. Furthermore, we seek to automate the segmentation and analysis process using machine learning.

Diabetic Tendinopathy

Diabetic Tendinopathy

Type II diabetes mellitus (T2DM) dramatically affects the baseline function of flexor tendons in the hand; up to 50% of diabetic patients experience impaired hand function, including increased rates of tenosynovitis, and carpal tunnel syndrome. In addition to decrements in tendon gliding function, deficits in mechanical properties are also observed, rendering diabetic tendons more susceptible to rupture.  Using a murine model of diet induced obesity we have recapitulated several aspects of the ‘diabetic hand syndrome’ observed clinically in diabetic patients and have demonstrated that reversing T2DM and restoring normal metabolic function is insufficient to halt the progress of diabetic tendinopathy, indicating the need for development of tendon specific treatment strategies.

Selected Publications

Complete List of Publications

Tendon Biology & Healing:

  • V Studentsova, K Mora, Glasner MF, MR Buckley, Loiselle AE. 2018. Obesity/ Type II Diabetes Promotes  Function-limiting Changes in Murine Tendons that are not Reversed by Restoring  Normal Metabolic Function.  Scientific Reports. 8(1): 9218.
  • JE Ackerman, KT Best, RJ O’Keefe, AE Loiselle. 2017. Deletion of EP4 in S100a4-lineage cells reduces adhesion formation during early but not the late stages of flexor tendon healing. Scientific Reports. 7(1):8658.
  • JE Ackerman, MB Geary, CA Orner, F Bawany, AE Loiselle. 2017.  Type II Diabetes Alters Macrophage Polarization Resulting in a Fibrotic Tendon Healing Response. PlosOne.12(7):e0181127.
  • JE Ackerman, I Bah, MR Buckley, AE Loiselle. 2017. Aging Does Not Alter Tendon Mechanical Properties During Homeostasis, but does Impair Flexor Tendon Healing. Journal of Orthopaedic​ Research. 35(12):2716-2724.
  • JE Ackerman, AE Loiselle. 2016. Murine Flexor Tendon Injury and Repair Surgery. Journal of Visualized Experiments. e54433, doi:10.3791/54433.
  • AE Loiselle, BJ Frisch, MJ Wolenski, JA Jacobson, LM Calvi, EM Schwarz, HA Awad, RJ O’Keefe.  2011.  Bone Marrow Derived Matrix Metalloproteinase-9 is Associated with Fibrous Adhesion Formation after Murine Flexor Tendon Injury. PlosOne. 7(7):e40602. 
  • AE Loiselle, GA Bragdon, JA Jacobson, S Hasslund, Z Cortes, DJ Mitten, EM Schwarz, HA Awad, RJ O’Keefe. 2009.  Remodeling of Murine Intrasynovial Tendon Adhesions Following Injury: Mmp and Neotendon Gene Expression. Journal of Orthopaedic Research. 27: 833-840.

Bone Biology & Regeneration:

  • Loiselle, AE; EM Paul, GS Lewis, HJ Donahue. 2012. Osteoblast and Osteocyte-Specific Loss of Connexin43 Results in Delayed Bone Formation and Healing During Murine Fracture Healing. Journal of Orthopaedic Research. 31(1): 147-54.
  • Loiselle AE; SA Lloyd, EM Paul, GS Lewis, HJ Donahue.  2013. Inhibition of GSK-3β Rescue the Impairments in Bone Formation and Mechanical Properties Associated with Fracture Healing in Osteoblast Selective Connexin 43 Deficient Mice. PlosOne. 8(11): e81399. 
  • Loiselle, AE; L Wei, M Faryad, J Gao, A Lakhtakia, HJ Donahue. 2013. Specific Biomimetic Hydroxyapatite Nanotopographies with Fractal Distributions Enhance Osteoblastic Differentiation and Bone Graft Osteointegration.  Tissue Eng. 19 (15-16): 1704-12. 
  • Xie, CX; BJ Li, M Xue, A Naik, A Lin, A Loiselle, EM Schwarz, R Guldberg, RJ O’Keefe, X Zhang.  2009. Rescue of Impaired Fracture Healing in COX-2-/- mice by Activation of Prostaglandin E2 Receptor Subtype 4. American Journal of Pathology. 175(2): 772-85. 

Selected Reviews

  • AE Loiselle, M Kelly, WC Hammert. 2015. Biological augmentation of flexor tendon repair: A challenging cellular Landscape. J Hand Surgery. 41(1):144-9.
  • Lim, JY+; AE Loiselle+, JS Lee, HJ Donahue.  2011. Optimizing the Osteogenic Potential of Adult Stem Cells Skeletal Regeneration.   Journal of Orthopaedic Research. 29(11): 1627-33.  
  • Loiselle, AE; JX Jiang, HJ Donahue. 2012. Gap Junction and Hemichannel Functions in Osteocytes.  Bone. 54(2): 205-12.
  • Govey, PM; AE Loiselle, HJ Donahue.  2013.  Biophysical Regulation of Stem Cell Differentiation. Current Osteoporosis Reports. 11 (2): 83-91.
  • Loiselle, AE; JX Jiang, HJ Donahue. 2012. Gap Junction and Hemichannel Functions in Osteocytes. Bone. 54(2): 205-12.
  • Lloyd, SA#; AE Loiselle#, Y Zhang, HJ Donahue. 2014. Shifting Paradigms on the Role of Connexin43 in the Skeletal Response to Mechanical Signals. Journal of Bone and Mineral Research. 29(2): 275-86. #Co-authorship.
  • AE Loiselle, M Kelly, WC Hammert. 2015. Biological augmentation of flexor tendon repair: A challenging cellular Landscape. J Hand Surgery. 41(1):144-9. PMID: 26652792.