RESEARCH PROGRAMS AND AFFILIATIONS
Etiology and Prevention of Loss of Fixation in Cemented Knee Replacements: (PI: KA Mann) The overall goal of this study is to provide a mechanistic and functional understanding of the role of mechanical interlock between cement and bone in TKA fixation, and determine if implant fixation can be improved by mitigating the loss of interlock through use of an established drug therapy. In this competitive renewal, we will develop a cemented tibial replacement model in the rat that recapitulates the cement-bone interlock that occurs in human arthroplasty. We will: 1) investigate alterations in the morphology and micro-mechanics of TKA cement-bone interlock as a function of time with in vivo service, 2) investigate dynamic bone remodeling and cellular response as a function of position in the interlocked construct, 3) determine the longitudinal effect aging/osteoporosis on morphology, micro-mechanics, and cellular changes of cement-bone interlock for TKA using an ovariectomy (OVX) model, 4) determine if systemic dosing of an antiresorptive agent (zoledronic acid) can prevent loss of TKA interlock in normal and OVX cases, and 5) determine if local dosing of zoledronic acid from PMMA cement in TKA can confer a positive effect as similar to systemic dosing. (NIH funded: 2017-2022)
Predicting bone fracture in patients with metastatic disease. (PIs: TA Damron , KA Mann) Primary tumors, such as breast and prostate cancer, can metastasize to bone cause bone destruction and bone fracture. Predicting whether a bone with metastatic disease will fracture remains a clinical challenge. Clinical scoring systems based on X-ray and patient pain levels are not good predictors for determining which bones require surgical stabilization. We are using Finite Element (FE) modeling of clinical CT scan sets in collaboration with Dr. Timothy Damron to determine activities of daily living that are predictive of fracture.The long term goal is to use FE as a tool to help surgeons decide which patients to stabilize from those that are not at risk of fracture. (Funding from Baldwin Foundation, 2016-2019)
Role of therapeutic radiation in increasing fracture risk of bone: (PI: T Damron) Using a murine model of radiation damage to the extremities we are investigating the implications of bony remodeling in terms of structure and fundamental changes to bone material fracture resistance and chemical changes to the bone. We are using biomechanical strength tests and fracture toughness tests to monitor changes in bone structure and material properties with time, radiation dose, and anabolic, antiresorptive and radioprotection treatments. We are also using a combination of voxel-based finite element modeling with material damage models and comparing these to experiments to gain a better understanding of bone ‘brittle’ behavior. (NIH funded: 2014-2021 NCE)
Reducing Post-Radiotherapy Bone Fragility Through Orchestrated Cell Survival (PI: ME Oest) Using an established mouse model of limited field, clinically relevant fractionated irradiation, this proposal will investigate the natural time course and pharmacologic modulation of RTx-induced bone fragility in terms of local and distant cellular, tissue, and mechanical functions. Specifically, the goals are to 1) use an in vitro approach to identify RTx-upregulation of cytokine production by primary marrow cells that may regulate bone damage outside the irradiated field, comparing human and murine responses; 2) characterize the progression of marrow progenitor cell damage and recovery cycles post-RTx, including osteoblastic and osteoclastic lineages; 3) determine the efficacy of PTH as a progenitor cell radioprotectant; and 4) evaluate a short, tailored PTH–ZA co-treatment for radioprotection of progenitor cells, normalizing matrix remodeling, and restoring bone strength. Our overall goal is to identify translatable strategies to preserve post-RTx local and systemic bone quality and strength long-term, compatible with the clinical manifestation of fragility fractures years post-RTx. (NIH funded: 2017-2022).
Recent Representative Publications
- Mann KA, Miller MA, Rossow JK, Tatusko ME, Horton JA, Damron TA, Oest ME. Progressive loss of implant fixation in a preclinical rat model of cemented knee arthroplasty. J Orthop Res 2020 Dec 31. PMID 33382095
- Bartlow CM, Mann KA, Damron TA, Oest ME. Altered mechanical behavior of demineralized bone following therapeutic radiation. J Orthop Res In Press, 2020. PMID: 32965711
- Mann KA, Miller MA, Tatusko ME, Oest ME. Similitude of cement-bone micromechanics in cemented rat and human knee replacement. J Orthop Res 38(7):1529-1537, 2020. PMID: 32167182
- Damron TA, Mann KA. Fracture risk assessment and clinical decision making for patients with metastatic bone disease. J Orthop Res 38(6): 1175-1190, 2020. PMID 32162711
- Mandair GS, Oest ME, Mann KA, Morris MD, Damron TA, Kohn DH. Radiation-induced changes to bone composition extend beyond periosteal bone. Bone Rep. 2020 Mar 28;12:100262. PMID 32258252
- Mann KA, Miller MA, Amendola RL, Cyndari K, Horton JA, Damron TA, Oest ME. Early changes in cement-bone fixation using a novel rat knee replacement model J Orthop Res 37(10): 2163-2171, 2019. PMID: 31206747
- Ordway NR, Ash KJ, Miller MA, Mann KA, Hayashi K. A biomechanical comparison of four hip arthroplasty designs in a canine model. Vet Comp Orthop Traumatol. 32(5): 369-375, 2019. PMID 31140184
- Liu C, Cabahug-Zuckerman P, Stubbs C, Pendola M, Cai C, Mann KA, Castillo AB. Mechanical loading promotes the expansion of primitive osteoprogenitors and organizes matrix and vascular morphology in long bone defects. J Bone Miner Res 34(5): 896-910, 2019.
- Damron TA, Mann KA. Evidence of negative effects of defect size and older patient age by quantitative CT-based 3D image analysis in ultraporous beta-tricalcium phosphate grafted extremity bone defects at one year. Adv Orthop Nov 1;2018:5304215, 2018.
- Bartlow CM, Mann KA, Damron TA, Oest ME. Limited field radiation therapy results in decreased bone fracture toughness in a murine model. PLoS One 13(10):e0204928, 2018.