Dr. Goodnough is an orthopaedic surgeon who is fellowship-trained in orthopaedic traumatology. This specialty is dedicated to the care of patients with complex injuries to the body’s bones, joints, or tissues.

Dr. Goodnough is a clinical instructor of orthopaedic surgery. He also holds a PhD degree, and his doctoral research focused on genetic mechanisms of early bone development.

For each patient, he develops a personalized plan of care. His goals are to treat the patient’s injury, restore function, and help promote the best possible quality of life. His clinical interests include nonunions, periarticular fractures, fractures of the pelvis and acetabulum, and infections.

Dr. Goodnough has conducted research on the role of skeletal stem cells in fracture healing. He also has investigated how cells function in fractures that have failed to heal (“nonunions”).

He has co-authored articles on his research discoveries in the Journal of the American Academy of Orthopaedic Surgery, Journal of Orthopaedic Trauma, Journal of Bone and Mineral Research, and elsewhere. Topics include advances in surgical technique and technology.

He also has contributed to chapters in the textbooks Surgery of the Hip, Skeletal Trauma of the Upper Extremity, and Operative Techniques in Orthopedic Trauma.

Dr. Goodnough has presented the findings of his research at numerous national and regional conferences. They include meetings of the Orthopaedic Trauma Association, American Academy of Orthopaedic Surgeons, and Western Orthopaedic Association. Topics have included the effects of non-steroidal anti-inflammatory drugs on skeletal stem cells in fractures.

Dr. Goodnough is a member of the American Academy of Orthopaedic Surgeons, Orthopaedic Trauma Association, and AO, the global network of doctors dedicated to the surgical treatment of trauma and musculoskeletal disorders.

Clinical Focus

  • Orthopaedic Trauma
  • Orthopaedic Surgery

Academic Appointments

Honors & Awards

  • Recipient, Orthopaedic Summit Resident Travel Grant
  • What’s New in Musculoskeletal Basic Science, Journal of Bone and Joint Surgery “Orthobuzz”
  • Resident Award, Western Orthopaedic Association Annual Meeting
  • Recipient, Depuy Synthes Travel Grant
  • Recipient, Foundations Orthopedic Trauma Travel Grant
  • Intern of the Year, Stanford Department of Vascular Surgery
  • Member, Alpha Omega Alpha Honors Society
  • Recipient, Doctoral Excellence Award in Pathology
  • Recognition, Graduate School, Case Western Reserve University School of Medicine (4.0 Cumulative GPA)
  • Representative, Case Western Reserve University Medical Science Training Program, National MD/PhD Conference
  • Finalist, Lindau Laureates
  • Best Poster, Musculoskeletal Research Day, Case Western Reserve University School of Medicine
  • Best Poster, MSTP Winter Retreat, Case Western Reserve University School of Medicine
  • Participant, National Institutes of Health Medical Scientist Training Program

Professional Education

  • Fellowship: Harborview Medical Center (2021) WA
  • Residency: Stanford University Orthopaedic Surgery Residency (2020) CA
  • Medical Education: Case Western Reserve School of Medicine (2015) OH

All Publications

  • Supplemental medial small fragment fixation adds stability to distal femur fixation: A biomechanical study. Injury Henry Goodnough, L., Salazar, B. P., Chen, M. J., Storaci, H., Guzman, R., Heffner, M., Tam, K., DeBaun, M. R., Gardner, M. J. 2021


    INTRODUCTION: Bridge plating of distal femur fractures with lateral locking plates is susceptible to varus collapse, fixation failure, and nonunion. While medial and lateral dual plating has been described in clinical series, the biomechanical effects of dual plating of distal femur fractures have yet to be clearly defined. The purpose of this study was to compare dual plating to lateral locked bridge plating alone in a cadaveric distal femur gap osteotomy model.MATERIALS AND METHODS: Gap osteotomies were created in eight matched pairs of cadaveric female distal femurs (average age: 64 yrs (standard deviation ± 4.4 yrs); age range: 57-68 yrs;) to simulate comminuted extraarticular distal femur fractures (AO/OTA 33A). Eight femurs underwent fixation with lateral locked plates alone and were matched with eight femurs treated with dual plating: lateral locked plates with supplemental medial small fragment non-locking fixation. Mechanical testing was performed on an ElectroPuls E10000 materials testing system using a 10kN/100 Nm biaxial load cell. Specimens were subject to 25,000 cycles of cyclic loading from 100-1000N at 2Hz.RESULTS: Two (2/8) specimens in the lateral only group failed catastrophically prior to completion of testing. All dual plated specimens survived the testing regimen. Dual plated specimens demonstrated significantly less coronal plane displacement (median 0.2 degrees, interquartile range [IQR], 0.0-0.5 degrees) compared to 2.0 degrees (IQR 1.9-3.3, p=0.02) in the lateral plate only group. Dual plated specimens demonstrated greater bending stiffness compared to the lateral plated group (median 29.0kN/degree, IQR 1.5-68.2kN/degree vs median 0.50kN/degree, IQR 0.23-2.28kN/degree, p=0.03).CONCLUSION: Contemporary fixation methods with a distal femur fractures are susceptible to mechanical failure and nonunion with lateral plates alone. Dual plate fixation in a cadaveric model of distal femur fractures underwent significantly less displacement under simulated weight bearing conditions and demonstrated greater stiffness than lateral plating alone. Given the significant clinical failure rates of lateral bridge plating in distal femur fractures, supplemental fixation should be considered, and dual plating of distal femurs augments mechanical stability in a clinically relevant magnitude.

    View details for DOI 10.1016/j.injury.2021.04.056

    View details for PubMedID 33985754

  • Indications for cement augmentation in fixation of geriatric intertrochanteric femur fractures: a systematic review of evidence. Archives of orthopaedic and trauma surgery Goodnough, L. H., Wadhwa, H., Tigchelaar, S. S., DeBaun, M. R., Chen, M. J., Graves, M. L., Gardner, M. J. 2021


    INTRODUCTION: Achieving durable mechanical stability in geriatric intertrochanteric proximal femur fractures remains a challenge. Concomitant poor bone quality, unstable fracture patterns, and suboptimal reduction are additional risk factors for early mechanical failure. Cement augmentation of the proximal locking screw or blade is one proposed method to augment implant anchorage. The purpose of this review is to describe the biomechanical and clinical evidence for cement augmentation of geriatric intertrochanteric fractures, and to elaborate indications for cement augmentation.METHODS: The PubMed database was searched for English language studies up to January 2021. Studies that assessed effect of calcium phosphate or methylmethacrylate cement augmentation during open reduction and internal fixation of intertrochanteric fractures were included. Studies with sample size<5, nontraumatic or periprosthetic fractures, and nonunion or revision surgery were excluded. Study selection adhered to PRISMA criteria.RESULTS: 801 studies were identified, of which 40 met study criteria. 9 studies assessed effect of cement augmentation on fracture displacement. All but one found that cement decreased fracture displacement. 10 studies assessed effect of cement augmentation on total load or cycles to failure. All but one demonstrated that augmented implants increased this variable. Complication rates of cement augmentation during ORIF of intertrochanteric fractures ranged from 0 to 47%, while non-augmented implants ranged from 0 to 51%. Reoperation rates ranged from 0 to 11% in the cement-augmented group and 0 to 11% in the non-augmented group. Fixation failure ranged from 0 to 11% in the cement-augmented group and 0 to 20% in the non-augmented group. Nonunion ranged from 0 to 3.6% in the cement-augmented group and 0 to 34% in the non-augmented group.CONCLUSIONS: Calcium phosphate or PMMA-augmented CMN fixation of IT fractures increased construct stability and improved outcomes in biomechanical and early clinical studies. The findings of these studies suggest an important role for cement augmentation in patient populations at high risk of mechanical failure.

    View details for DOI 10.1007/s00402-021-03872-6

    View details for PubMedID 33829301

  • White-Light Body Scanning Captures Three-Dimensional Shoulder Deformity After Displaced Diaphyseal Clavicle Fracture. Journal of orthopaedic trauma DeBaun, M. R., Lai, C., Schultz, B. J., Oquendo, Y. A., Campbell, S. T., Goodnough, L. H., Bishop, J. A., Gardner, M. J. 2021; 35 (4): e142–e147


    OBJECTIVE: We sought to determine if white-light three-dimensional (3D) body scanning can identify clinically relevant shoulder girdle deformity after displaced diaphyseal clavicle fracture (DCF).METHODS: Adult patients with DCF (OTA/AO 15A) were prospectively enrolled. Four subcutaneous osseous landmarks were used to measure shoulder girdle morphology of the injured and uninjured shoulder. Measurements were made both manually with a tape measure and digitally with a white-light 3D scanner. Bilateral radiographs were obtained, and clavicle length was recorded. Quick-Disabilities of the Arm, Shoulder, and Hand surveys were administered at injury and at 6 and 12 weeks.RESULTS: Twenty-two patients were included in the study. At the initial visit, all patients had significant differences in deformity measurements between injured and uninjured shoulders as measured by 3D scanning. There was no difference between shoulders measured using manual measurements. At 6 and 12 weeks, shoulder asymmetry was significantly less in patients treated with surgery compared with nonoperative patients as measured by the 3D scanner alone. Clavicle shortening measured on 3D scanning had weak and moderate positive correlations to radiographs (R = 0.27) and manual measurements (R = 0.53), respectively. Patients treated with surgery had significant functional improvements by 6 weeks, and a similar improvement was not seen until 12 weeks in nonsurgical patients.CONCLUSION: White-light 3D scanning was able to identify and monitor clinically relevant shoulder girdle deformity after DCF. This tool may become a useful adjunct to clinical examination and radiographic assessment, when determining clinically relevant deformity thresholds. In the future, quantifying and understanding shoulder deformity may inform clinical decision making in these patients.LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

    View details for DOI 10.1097/BOT.0000000000001957

    View details for PubMedID 32910627

  • Medial Column Support in Pilon Fractures Using Percutaneous Intramedullary Large Fragment Fixation. Journal of orthopaedic trauma Goodnough, L. H., Tigchelaar, S. S., Van Rysselberghe, N. L., DeBaun, M. R., Gardner, M. J., Hecht, G. G., Lucas, J. F. 2021

    View details for DOI 10.1097/BOT.0000000000002073

    View details for PubMedID 33675625

  • Cephalomedullary helical blade is independently associated with less collapse in intertrochanteric femur fractures than lag screws. European journal of orthopaedic surgery & traumatology : orthopedie traumatologie Goodnough, L. H., Wadhwa, H., Tigchelaar, S. S., Pfaff, K., Heffner, M., Van Rysselberghe, N., DeBaun, M. R., Bishop, J. A., Gardner, M. J. 2021


    OBJECTIVES: Excessive fracture site collapse and shortening in intertrochanteric femur fractures alter hip biomechanics and patient outcomes. The purpose of the study was to compare extent of collapse in cephalomedullary nails with blades or lag screws. We hypothesized that there would be no difference in collapse between helical blades and lag screws.DESIGN: Retrospective cohort study.SETTING: Single U.S. Level I Trauma Center.PATIENTS: 171 consecutive patients treated with cephalomedullary nails with either lag screw or blade for AO/OTA 31A1-3 proximal femur fractures and minimum 3-month follow-up.INTERVENTION: Lag screw or helical blade in a cephalomedullary nail.OUTCOME MEASURES: The primary outcome was fracture site collapse at 3months.RESULTS: There was a significantly higher proportion of reverse-oblique and transverse intertrochanteric femur fractures (31-A3) in the lag screw group (15/42 vs 25/129). A3 patterns were associated with more collapse. There was significantly less collapse in the blade group (median 4.7mm, inter-quartile range 2.5-7.8mm) than the screw group (median 8.4 mmm, inter-quartile range 3.7-11.2mm, p 0.006). Median collapse was no different between blades and screws when comparing stable and unstable patterns. However, blades were independently associated with 2.5mm less collapse (95%CI -4.2, -0.72mm, p 0.006) and lower likelihood of excessive collapse (>10mm at 3months, OR 0.3, 95% CI 0.13-0.74, p 0.007), regardless of fracture pattern.CONCLUSIONS: Helical blades are independently associated with significantly less collapse than lag screws in intertrochanteric proximal femur fractures, after adjusting for unstable fracture patterns. In fracture patterns at risk for collapse, surgeons can consider use of a helical blade due to its favorable sliding properties compared to screws.

    View details for DOI 10.1007/s00590-021-02875-8

    View details for PubMedID 33587180

  • Short versus long cephalomedullary nailing of intertrochanteric fractures: a meta-analysis of 3208 patients. Archives of orthopaedic and trauma surgery Cinque, M. E., Goodnough, L. H., Md, B. J., Fithian, A. T., DeBaun, M. n., Lucas, J. F., Md, M. J., Bishop, J. A. 2021


    The purpose of the study was to compare treatment outcomes after short or long cephalomedullary nailing for intertrochanteric femur fractures.A systematic review of perioperative outcomes after short or long cephalomedullary nailing for intertrochanteric femur fractures was performed. The following databases were used: using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (1980-2019), and MEDLINE (1980-2019). The queries were performed in June 2019.The following search term query was used: "Intramedullary Nail AND Intertrochanteric Fracture OR "Long OR Short Nail AND intertrochanteric Fracture." Studies were excluded if they were "single-arm" studies (i.e., reporting on either long or short CMN but not both), or did not report at least one of the outcomes being meta-analyzed. Furthermore, cadaveric studies, animal studies, basic science articles, editorial articles, surveys and studies were excluded.Two investigators independently reviewed abstracts from all identified articles. Full-text articles were obtained for review if necessary, to allow further assessment of inclusion and exclusion criteria. Additionally, all references from the included studies were reviewed and reconciled to verify that no relevant articles were missing from the systematic review.Short nails were associated with statistically significantly less estimated blood loss and operative time compared to long nails. There were no significant differences in transfusion rates, implant failures or overall re-operation rates between implant lengths. Similarly, there was no significant difference in peri-implant fracture between implant lengths.Overall, the available clinical evidence supports the use of short cephalomedullary nails for the majority of intertrochanteric femur fractures.Meta-analysis; Level III, therapeutic.

    View details for DOI 10.1007/s00402-021-03752-z

    View details for PubMedID 33484311

  • Incidence and Management of Articular Impaction in Geriatric Olecranon Fractures. The Journal of the American Academy of Orthopaedic Surgeons Wadhwa, H. n., Goodnough, L. H., Finlay, A. K., DeBaun, M. R., Campbell, S. T., Hecht, G. n., Lucas, J. F., Bishop, J. A., Gardner, M. J. 2021


    Olecranon fractures are common in the elderly. Articular impaction is encountered occasionally, but the incidence and outcomes after treatment of this injury pattern have not been well characterized.We evaluated a cohort of geriatric olecranon fractures to determine the incidence of articular impaction and describe a technique for open reduction and internal fixation.Of the 63 patients in our series, 31 had associated intraarticular impaction (49.2%). Patients with articular impaction did not have significantly different rates of postoperative complications (11/31, 35.5% versus 10/31, 32.3%; P = 1.00) or revision surgery (10/31, 32.3% versus 8/31, 25.8%; P = 0.780) compared with those without articular impaction.Articular impaction is a common feature of geriatric olecranon fractures. Surgeons must maintain a high index of suspicion and have a surgical plan in place for managing this component of the injury.

    View details for DOI 10.5435/JAAOS-D-20-01293

    View details for PubMedID 33999874

  • Distal Femur Replacement versus Open Reduction and Internal Fixation for Treatment of Periprosthetic Distal Femur Fractures: Systematic Review and Meta-Analysis. Journal of orthopaedic trauma Wadhwa, H. n., Salazar, B. P., Goodnough, L. H., Van Rysselberghe, N. L., DeBaun, M. R., Wong, H. N., Gardner, M. J., Bishop, J. A. 2021


    To compare complications and functional outcomes of treatment with primary distal femoral replacement (DFR) versus open reduction and internal fixation (ORIF).PubMed, Embase, and Cochrane databases were searched for English language studies up to May 19, 2020, identifying 913 studies.Studies that assessed complications of periprosthetic distal femur fractures with primary DFR or ORIF were included. Studies with sample size ≤5, mean age <55, nontraumatic indications for DFR, ORIF with non-locking plates, native distal femoral fractures, or revision surgeries were excluded. Selection adhered to PRISMA criteria.Study quality was assessed using previously reported criteria. There were 40 Level IV studies, 17 Level III studies, and 1 Level II study.Fifty-eight studies with 1,484 patients were included in the meta-analysis. Complications assessed (Incidence Rate Ratio (IRR) (95%CI): 0.78 (0.59-1.03)) and reoperation or revision (IRR (95%CI): 0.71 (0.49-1.04)) were similar between the DFR and ORIF cohorts. Mean knee range of motion (ROM) was greater in the ORIF cohort (DFR: 90.47 vs. ORIF: 100.36, p < 0.05). Mean Knee Society Score (KSS) (DFR: 79.41 vs. ORIF: 82.07, p = 0.35) and return to preoperative ambulatory status were similar (IRR (95%CI): 0.82 (0.48-1.41)).In comparing complications among patients treated for periprosthetic distal femur fracture with DFR or ORIF, there was no difference between the groups. There were also no differences in functional outcomes, although knee ROM was greater in the ORIF group. This systematic review and meta-analysis highlights the need for future prospective trials evaluating the outcomes of these divergent treatment strategies.Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

    View details for DOI 10.1097/BOT.0000000000002141

    View details for PubMedID 34001801

  • Lateral Distractor Use During Internal Fixation of Tibial Plateau Fractures Has Minimal Risk of Iatrogenic Peroneal Nerve Palsy. Journal of orthopaedic trauma Chen, M. J., Salazar, B. P., Tigchelaar, S. S., Frey, C. S., DeBaun, M. R., Goodnough, L. H., Bellino, M. J., Bishop, J. A., Gardner, M. J. 2020


    OBJECTIVES: To determine the incidence of iatrogenic peroneal nerve palsy after application of an intraoperative lateral distractor during open reduction and internal fixation (ORIF) of tibial plateau fractures (TPF).DESIGN: Retrospective review.SETTING: Single academic Level I trauma center.PATIENTS: One hundred and forty-seven patients met criteria and were included in the study.INTERVENTION: Patients with unicondylar and bicondylar TPFs underwent ORIF and received application of an intraoperative lateral distractor to aid in visualization and reduction of the impacted lateral plateau.MAIN OUTCOME MEASUREMENTS: Incidence of iatrogenic peroneal nerve palsy.RESULTS: There was a 2.0% incidence of iatrogenic peroneal nerve symptoms (three of 147 patients), the majority of which were incomplete sensory deficits. There was no association with staged external fixation, regional anesthesia, or tourniquet use.CONCLUSION: Use of an intraoperative lateral distractor is safe and has a low incidence of iatrogenic peroneal nerve palsy if applied carefully.LEVEL OF EVIDENCE: Prognostic level IV. See Instructions for Authors for a complete description of levels of evidence.

    View details for DOI 10.1097/BOT.0000000000001875

    View details for PubMedID 33165211

  • Delayed Union of a Diaphyseal Forearm Fracture Associated With Impaired Osteogenic Differentiation of Prospectively Isolated Human Skeletal Stem Cells. JBMR plus Goodnough, L. H., Ambrosi, T. H., Steininger, H., DeBaun, M. R., Abrams, G. D., McAdams, T. R., Gardner, M. J., Chan, C. K., Bishop, J. A. 2020; 4 (10): e10398


    Delayed union or nonunion are relatively rare complications after fracture surgery, but when they do occur, they can result in substantial morbidity for the patient. In many cases, the etiology of impaired fracture healing is uncertain and attempts to determine the molecular basis for delayed union and nonunion formation have been limited. Prospectively isolating skeletal stem cells (SSCs) from fracture tissue samples at the time of surgical intervention represent a feasible methodology to determine a patient's biologic risk for compromised fracture healing. This report details a case in which functional in vitro readouts of SSCs derived from human fracture tissue at time of injury predicted a poor fracture healing outcome. This case suggests that it may be feasible to stratify a patient's fracture healing capacity and predict compromised fracture healing by prospectively isolating and analyzing SSCs during the index fracture surgery. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

    View details for DOI 10.1002/jbm4.10398

    View details for PubMedID 33103027

  • Human skeletal stem cell aging. Aging Ambrosi, T. H., Goodnough, L. H., Chan, C. K. 2020

    View details for DOI 10.18632/aging.104034

    View details for PubMedID 32929053

  • Distal Femur Replacement versus Surgical Fixation for the Treatment of Geriatric Distal Femur Fractures: A Systematic Review. Journal of orthopaedic trauma Salazar, B. P., Babian, A. R., DeBaun, M. R., Githens, M. F., Chavez, G. A., Goodnough, H., Gardner, M. J., Bishop, J. A. 2020


    OBJECTIVES: The management of geriatric distal femur fractures is controversial, and both primary distal femur replacement (DFR) or surgical fixation (SF) are viable treatment options. The purpose of this study was to compare patient outcomes after these treatment strategies.DATA SOURCES: PubMed, Embase, and Cochrane databases were searched for English language papers up to April 24, 2020, identifying 2,129 papers.STUDY SELECTION: Studies evaluating complications in elderly patients treated for distal femur fractures with either immediate DFR or surgical fixation were included. Studies with mean patient age <55 years, nontraumatic indications for DFR, or SF with non-locking plates were excluded.DATA EXTRACTION: Two studies provided Level II or III evidence while the remaining 28 studies provided Level IV evidence. Studies were formally evaluated for methodologic quality using established criteria. Treatment failure between groups was compared using an incidence rate ratio.DATA SYNTHESIS: Treatment failure was defined for both surgical fixation and arthroplasty as complications requiring a major reoperation for reasons such as mechanical failure, nonunion, deep infection, aseptic loosening, or extensor mechanism disruption. There were no significant differences in complication rates or knee range of motion between SF and DFR.CONCLUSION: SF and DFR for the treatment of geriatric distal femur fractures demonstrate similar overall complication rates. Given the available evidence, no strong conclusions on the comparative effectiveness between the two treatments can be definitively made. More rigorous prospective research comparing SF versus DFR to treat acute geriatric distal femur fractures is warranted.LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

    View details for DOI 10.1097/BOT.0000000000001867

    View details for PubMedID 32569072

  • Geriatric fragility fractures are associated with a human skeletal stem cell defect. Aging cell Ambrosi, T. H., Goodnough, L. H., Steininger, H. M., Hoover, M. Y., Kim, E., Koepke, L. S., Marecic, O., Zhao, L., Seita, J., Bishop, J. A., Gardner, M. J., Chan, C. K. 2020: e13164


    Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age-related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate intrinsic functional defects that drive impaired healing. Using flow cytometry, we analyzed and isolated hSSCs from callus tissue of five different skeletal sites (n=61) of patients ranging from 13 to 94years of age for functional and molecular studies. We observed that fracture-activated amplification of hSSC populations was comparable at all ages. However, functional analysis of isolated stem cells revealed that advanced age significantly correlated with reduced osteochondrogenic potential but was not associated with decreased in vitro clonogenicity. hSSCs derived from women displayed an exacerbated functional decline with age relative to those of aged men. Transcriptomic comparisons revealed downregulation of skeletogenic pathways such as WNT and upregulation of senescence-related pathways in young versus older hSSCs. Strikingly, loss of Sirtuin1 expression played a major role in hSSC dysfunction but re-activation by trans-resveratrol or a small molecule compound restored in vitro differentiation potential. These are the first findings that characterize age-related defects in purified hSSCs from geriatric fractures. Our results provide a foundation for future investigations into the mechanism and reversibility of skeletal stem cell aging in humans.

    View details for DOI 10.1111/acel.13164

    View details for PubMedID 32537886

  • Complication Rates after Lateral Plate Fixation of Periprosthetic Distal Femur Fractures: A Multicenter Study. Injury Campbell, S. T., Lim, P. K., Kantor, A. H., Gausden, E. B., Goodnough, L. H., Park, A. Y., Bishop, J. A., Achor, T. S., Scolaro, J. A., Gardner, M. J. 2020


    OBJECTIVE: Periprosthetic fractures of the distal femur can be challenging injuries to treat; nonunion rates of up to 22% have been reported. The purpose of this study was to determine the rate of complications and nonunion in a multicenter series, and to identify patient or surgical factors that were associated with nonunion.DESIGN: Retrospective comparative study SETTING: Three Level 1 trauma centers PATIENTS: Fifty-five patients with a periprosthetic distal femur fracture proximal to a total knee arthroplasty. Minimum follow up for inclusion was six months or until union or failure.INTERVENTION: Surgical fixation using a precontoured lateral locking plate MAIN OUTCOME MEASUREMENT: Fracture union was the primary outcome. Patient demographic and injury variables (age, comorbidities, fracture classification and characteristics) and surgical technique factors (mode of plate fixation, plate material, working length, screw density, and proximal screw type) were identified and compared between patients who developed a nonunion and those who did not. Regression analysis was performed to identify independent risk factors for nonunion.RESULTS: The overall rate of nonunion was 18% and the total complication rate was 24%. After additional surgery, 49 of 55 patients went on to heal (89%). There were no statistical differences in patient demographic or injury variables between the union and nonunion groups, and none of the variables studied were independent risk factors for nonunion in the regression analysis.CONCLUSIONS: In this series of 55 patients with periprosthetic distal femur fractures treated with precontoured lateral locking plates, 18% developed nonunion and the overall complication rate was 24%. No patient or surgical variables were identified as risk factors. Future research should seek to identify patients at high risk for complication and nonunion who could benefit from alternative fixation strategies or distal femoral replacement.

    View details for DOI 10.1016/j.injury.2020.05.009

    View details for PubMedID 32482424

  • How do pilon fractures heal? An analysis of dual plating and bridging callus formation. Injury Campbell, S. T., Goodnough, L. H., Salazar, B., Lucas, J. F., Bishop, J. A., Gardner, M. J. 2020


    OBJECTIVES: 1) To determine the effect of single versus dual plate metaphyseal fixation for pilon fractures on callus formation and reoperation rates, 2) to determine the effect of biomechanically matched versus unmatched fixation, and 3) to determine whether patient or surgical factors were independent predictors of bridging callus formation or need for reoperation.DESIGN: Retrospective comparative study.SETTING: Single level one trauma center.PATIENTS: Fifty patients with AO/OTA type C2 or C3 pilon fractures treated with plate fixation.INTERVENTION: Internal fixation with a plate and screw construct, with comparisons made between patients with single versus dual plate fixation, and patients treated with biomechanically matched or unmatched fixation.MAIN OUTCOME MEASUREMENTS: Modified RUST (mRUST) scores at three and six months and reoperation rate.RESULTS: At six months, mean mRUST scores were significantly lower in patients treated with dual metaphyseal plates compared to a single plate (8.7 vs 10.4, p=0.046) There were 15 open fractures; eight were treated with supplemental fixation, while seven were treated with single-column fixation. Open fracture (OR 51.05, p=0.008) was a risk factor for reoperation. Screw density between 0.4 and 0.5 was a protective factor against reoperation (OR 0.03, p=0.026). Biomechanically unmatched fixation did not affect mRUST scores or reoperation rates.CONCLUSIONS: Pilon fractures treated with a single plate had more callus formation six months after surgery compared to those treated with dual plate fixation, and there was no difference in reoperation rates. Screw density between 0.4-0.5 was protective against reoperation. These data may serve as the basis of future work to determine the ideal fixation construct for the frequently comminuted metaphysis in pilon fractures. Further work is necessary to determine whether callus formation in these injuries is desirable.LEVEL OF EVIDENCE: Three.

    View details for DOI 10.1016/j.injury.2020.04.023

    View details for PubMedID 32434713

  • Selective screw fixation is associated with early failure of primary acetabular components for aseptic loosening. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Henry Goodnough, L., Bonano, J. C., Finlay, A. K., Aggarwal, V., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2020


    Selective augmentation of the acetabular component with screws during primary total hip arthroplasty (THA) assumes that the surgeon can detect when an acetabular component needs added stability. In contrast, non-selective screw users do not alter their practice based on their interpretation of stability and either use screws all or none of the time. We aimed to determine the effect of selective screw use on aseptic acetabular component loosening. We retrospectively reviewed aseptic failures of THA acetabular components. We compared the survivorship of selective to non-selective supplementation of acetabular fixation with screws, and compared time to revision, obesity and selective screw use. Selective screw use (n=16) was associated with earlier acetabular component aseptic loosening (median 1.9 years; interquartile range (IQR) 1.1-5.0) compared to non-selective screw use (n=22; median 5.6 years; IQR 2.0- 15.3, p = 0.010). Selective screw use was independently associated with earlier revision after adjusting for patient obesity. Obesity was associated with selective screw use in 50% of the cases versus 14% of non-selective cases (OR 6.3 CI 1.2-25.2, p = 0.028), possibly reflecting the increased difficulty in achieving acetabular component stability in this and other settings with compromised bone. Surgeons should carefully assess component stability at time of primary THA. If the acetabulum is not stable, the addition of screws alone may not be sufficient for acetabular component stability. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/jor.24649

    View details for PubMedID 32157712

  • Is percutaneous screw fixation really superior to non-operative management after valgus-impacted femoral neck fracture: a retrospective cohort study. European journal of orthopaedic surgery & traumatology : orthopedie traumatologie Goodnough, L. H., Wadhwa, H. n., Fithian, A. T., DeBaun, M. R., Campbell, S. T., Gardner, M. J., Bishop, J. A. 2020


    The optimal management of valgus-impacted femoral neck fractures remains controversial. Internal fixation is associated with significant rates of re-operation, while historical non-operative management strategies consisting of prolonged bed rest also resulted in patient morbidity. Our hypothesis was that screw fixation would have comparable failure rates to non-operative treatment and immediate mobilization for valgus-impacted femoral neck fractures.Retrospective cohort at a single academic Level I trauma center of patients with valgus-impacted femoral neck fractures (AO/OTA 31-B1) treated with percutaneous screw fixation (n = 97) or non-operatively (n = 28). Operative treatment consisted of percutaneous screw fixation. Non-operative treatment consisted of early mobilization. The primary outcome was a salvage operation. Patient demographics were assessed between groups.More non-operatively treated patients were permitted unrestricted weight-bearing (WBAT; p = 0.002). There was no increase in complication rates or mortality, and return to previous ambulatory status was comparable between operatively and non-operatively treated patients. 35.7% (10/28) of non-operatively treated patients underwent a subsequent operation, compared to 15.5% (15/97) of patients with screw fixation (p = 0.03). Only WBAT was independently associated with treatment failure (OR 3.1, 95%CI 1.2-8.3, p =0.02). WBAT was predictive of treatment failure only in the non-operatively treated group (64.3%, 9/14 WBAT vs 8.3%, 1/12 partial, p =0.005).After controlling for weight-bearing restrictions, we found no difference in failure rates between non-operative treatment and screw fixation. Non-operative treatment with partial weight-bearing had low failure rates, comparable complication and mortality rates, and equivalent functional outcomes to operative treatment and is reasonable if a patient would like to avoid surgery and accepts the risk of subsequent arthroplasty. Overall, there were relatively high failure rates in all groups.

    View details for DOI 10.1007/s00590-020-02742-y

    View details for PubMedID 32710126

  • Trochanteric fixation nail advanced with helical blade and cement augmentation: early experience with a retrospective cohort. European journal of orthopaedic surgery & traumatology : orthopedie traumatologie Goodnough, L. H., Wadhwa, H. n., Tigchelaar, S. S., DeBaun, M. R., Chen, M. J., Bishop, J. A., Gardner, M. J. 2020


    Intra-articular screw cut-out is a potential complication of intertrochanteric femur fracture fixation with a cephalomedullary nail. Cement augmentation of fixation in the proximal segment offers the prospect of increased stability and fewer complications, but clinical experience with non-resorbable cement is limited. To determine the handling properties and efficacy of this new technique, we performed a retrospective propensity-matched cohort of forty-four geriatric intertrochanteric femur fractures treated with a cephalomedullary nail with (n = 11) or without (n = 33) augmentation with non-resorbable cement injected into the proximal segment. In the patients treated with cement augmentation, at minimum 3-month follow-up, there were no instances of intra-articular cut-out, and no increase in re-operation compared to conventional fixation. Cement augmentation appears to be safe and effective in geriatric intertrochanteric femur fractures to mitigate risk of cut-out.

    View details for DOI 10.1007/s00590-020-02762-8

    View details for PubMedID 32804288

  • How are peri-implant fractures below short versus long cephalomedullary nails different? European journal of orthopaedic surgery & traumatology : orthopedie traumatologie Goodnough, L. H., Salazar, B. P., Furness, J. n., Feng, J. E., DeBaun, M. R., Campbell, S. T., Lucas, J. F., Cross, W. W., Leucht, P. n., Grant, K. D., Gardner, M. J., Bishop, J. A. 2020


    Cephalomedullary nails are a commonly used implant for the treatment of many pertrochanteric femur fractures and are available in short and long configurations. There is no consensus on ideal nail length. Relative advantages can be ascribed to short and long intramedullary nails, yet both implant styles share the potentially devastating complication of peri-implant fracture. Determining the clinical sequelae after fractures below nails of different lengths would provide valuable information for surgeons choosing between short or long nails. Thus, the purpose of the study was to compare injury patterns and treatment outcomes following peri-implant fractures below short or long cephalomedullary nails.This was a multicenter retrospective cohort study that identified 33 patients referred for treatment of peri-implant fractures below short and long cephalomedullary nails (n = 19 short, n = 14 long). We compared fracture pattern, treatment strategy, complications, and outcomes between these two groups.Short nails were associated with more diaphyseal fractures (odds ratio [OR] 13.75, CI 2.2-57.9, p 0.002), which were treated more commonly with revision intramedullary nailing (OR, infinity; p 0.01), while long nails were associated with distal metaphyseal fractures (OR 13.75, CI 2.2-57.9, p 0.002), which were treated with plate and screw fixation (p 0.002). After peri-implant fracture, there were no differences in blood loss, operative time, weight bearing status, or complication rates based on the length of the initial nail. In patients treated with revision nailing, there was greater estimated blood loss (EBL, median 300 cc, interquartile range [IQR] 250-1200 vs median 200 cc, IQR 100-300, p 0.03), blood product utilization and complication rates (OR 11.1, CI 1.1-135.7, p 0.03), but a trend toward unrestricted post-operative weight-bearing compared to patients treated with plate and screw constructs.Understanding fracture patterns and patient outcomes after fractures below nails of different lengths will help surgeons make more informed implant choices when treating intertrochanteric hip fractures. Revision to a long nail for the treatment of fractures at the tip of a short nail may be associated with increased patient morbidity.

    View details for DOI 10.1007/s00590-020-02785-1

    View details for PubMedID 32909108

  • Metaphyseal callus formation in pilon fractures is associated with loss of alignment: Is stiffer better? Injury Van Rysselberghe, N. L., Campbell, S. T., Goodnough, L. H., Salazar, B. P., Bishop, J. A., Bellino, M. J., Lucas, J. F., Gardner, M. J. 2020


    To assess the relationship between metaphyseal callus formation and preservation of distal tibial alignment in pilon fractures treated with internal plate fixation.Retrospective Review SETTING: Academic Level I Trauma Center PATIENTS: Forty-two patients with AO/OTA type C2 or C3 pilon fractures treated with plate fixation.Internal fixation with anterolateral plating, medial plating, or both. Modified Radiographic Union Score in Tibial fracture (mRUST) scores were determined from six-month radiographs.Change in lateral and anterior distal tibial angles (LDTA and ADTA) at six months post-operatively.High callus formation (mRUST ≥ 11 at six months) was associated with a greater loss of coronal reduction as measured by LDTA compared to low callus formation (mRUST < 11): 3.8 vs 2.1° (p = .019), with no difference in ADTA change between groups. In a multivariable logistic regression controlling for age, smoking, obesity, and open fracture, higher mRUST scores were a predictor of coronal reduction loss of five or more degrees (OR 1.71, p=.039). Dual column plating did not independently predict maintenance of alignment.Recent literature has popularized dual column fixation for pilon fractures, but it remains unknown whether increased metaphyseal stiffness enhances or impairs healing. In this series, decreased metaphyseal callus formation was associated with maintained coronal alignment, suggesting that a stiffer mechanical environment may be preferable to prevent short term reduction loss in these complex injuries.III.

    View details for DOI 10.1016/j.injury.2020.10.080

    View details for PubMedID 33097204

  • Dual Mini-Fragment Plating is Comparable to Precontoured Small Fragment Plating for Operative Diaphyseal Clavicle Fractures: A Retrospective Cohort Study. Journal of orthopaedic trauma DeBaun, M. R., Chen, M. J., Campbell, S. T., Goodnough, L. H., Lai, C., Salazar, B. P., Bishop, J. A., Gardner, M. J. 2019


    OBJECTIVES: To compare precontoured (Pc) small fragment plating to dual mini-fragment plating (DmF) for open reduction and internal fixation (ORIF) of diaphyseal clavicle fractures.DESIGN: Retrospective Cohort SETTING:: Level 1 Trauma CenterPatients/Participants: A total of 133 patients with displaced fractures of the diaphyseal clavicle (OTA/AO 15-B1, -2, and -3) treated with ORIF with a minimum of 1 year follow up or until radiographic and clinical union.INTERVENTION: Two patient cohorts were identified: 1) patients treated with orthogonal DmF plate constructs and 2) patients treated with Pc clavicle-specific plates.OUTCOME MEASUREMENTS: Union rate and implant removal were assessed using standard descriptive statistics. Odds ratios (OR), 95% confidence intervals (CI), and p-values (p) were calculated.RESULTS: There were 60 DmF and 74 Pc patients. There were no significant differences between groups with respect to age, gender, surgeon, body mass index, or mode of fixation. There was no significant difference in union (98.3% DmF; 100% Pc, p=0.45) or maintenance of reduction (98.3% DmF; 100% Pc, p=0.45). A total of 8% of DmF patients had symptomatic implant removal compared to 20% of Pc patients (OR 0.36, CI 0.12-1.05, p=0.061).CONCLUSIONS: This retrospective comparative study found no difference in union or maintenance of reduction for diaphyseal clavicle fractures fixed with DmF compared to Pc plating. Patients treated with DmF plates may have lower rates of symptomatic implant removal.LEVEL OF EVIDENCE: Therapeutic Level III.

    View details for DOI 10.1097/BOT.0000000000001727

    View details for PubMedID 31868765

  • Rates of Perioperative Complications Among Patients Undergoing Orthopedic Trauma Surgery Despite Having Positive Results for Methamphetamine ORTHOPEDICS Githens, T., DeBaun, M. R., Campbell, S. T., Wu, E. J., Goodnough, L., Lichstein, P., Painter, C., Krygier, J. E., Bishop, J., Gardner, M. J. 2019; 42 (4): 192–96


    The burden of psychosocial problems, including substance abuse, is high among trauma patients. Use of illicit substances is often noted during urine toxicology screening on admission and can delay surgery because of concerns for an interaction with anesthesia. Methamphetamine theoretically has potential to increase perioperative anesthetic risks. However, the authors are unaware of any studies documenting increased rates of cardiovascular complications in the perioperative period among orthopedic trauma patients. This study sought to determine the rate of cardiovascular complications in these patients. The authors reviewed the medical records of all patients between 2013 and 2018 who underwent orthopedic trauma surgery at two level I trauma centers in the setting of a methamphetamine-positive urine toxicology screening prior to surgery. Information on demographics, injury, type of surgical intervention, and incidence of perioperative cardiovascular and overall medical complications prior to discharge was recorded. Ninety-four patients were included in the study (mean age, 44 years; range, 16-78 years). Twenty-six (28%) patients had multiple injuries. Thirteen (14%) patients had debridement and/or provisional stabilization of an open or unstable fracture, 18 (19%) had treatment for an infection, and 63 (67%) had definitive fracture surgery. The overall rates of perioperative cardiovascular complications and perioperative medical complications were 2.1% and 3.2%, respectively. This study provides both a baseline understanding of the complication rate for methamphetamine-positive orthopedic trauma patients during general anesthesia and justification for larger multicenter studies to further investigate this topic. [Orthopedics. 2019; 42(4):192-196.].

    View details for DOI 10.3928/01477447-20190523-01

    View details for Web of Science ID 000476648200015

    View details for PubMedID 31136677

  • Changing practice patterns: flexed versus semi-extended positioning for tibial nailing CURRENT ORTHOPAEDIC PRACTICE Goodnough, L., Campbell, S. T., Githens, M. F., Gardner, M. J., Bishop, J. A. 2019; 30 (4): 356–60
  • Geriatric olecranon fractures treated with plate fixation have low complication rates CURRENT ORTHOPAEDIC PRACTICE Campbell, S. T., DeBaun, M. R., Goodnough, L., Bishop, J. A., Gardner, M. J. 2019; 30 (4): 353–55
  • Decreased estimated blood loss in lateral trans-psoas versus anterior approach to lumbar interbody fusion for degenerative spondylolisthesis. Journal of spine surgery (Hong Kong) Goodnough, L. H., Koltsov, J., Wang, T., Xiong, G., Nathan, K., Cheng, I. 2019; 5 (2): 185–93


    Background: The goal of the current study was to compare the perioperative and post-operative outcomes of eXtreme lateral trans-psoas approach (XLIF) versus anterior lumbar interbody fusion (ALIF) for single level degenerative spondylolisthesis. The ideal approach for degenerative spondylolisthesis remains controversial.Methods: Consecutive patients undergoing single level XLIF (n=21) or ALIF (n=54) for L4-5 degenerative spondylolisthesis between 2008-2012 from a single academic center were retrospectively reviewed. Groups were compared for peri-operative data (estimated blood loss, operative time, adjunct procedures or additional implants), radiographic measurements (L1-S1 cobb angle, disc height, fusion grade, subsidence), 30-day complications (infection, DVT/PE, weakness/paresthesia, etc.), and patient reported outcomes (leg and back Numerical Rating Scale, and Oswestry Disability Index).Results: Estimated blood loss was significantly lower for XLIF [median 100; interquartile range (IQR), 50-100 mL] than for ALIF (median 250; IQR, 150-400 mL; P<0.001), including after adjusting for significantly higher rates of posterior decompression in the ALIF group. There were no significant differences in rates of complications within 30 days, radiographic outcomes, or in re-operation rates. Both groups experienced significant pain relief post-operatively.Conclusions: The lateral trans-psoas approach is associated with diminished blood loss compared to the anterior approach in the treatment of degenerative spondylolisthesis. We were unable to detect differences in radiographic outcomes, complication rates, or patient reported outcomes. Continued efforts to directly compare approaches for specific indications will minimize complications and improve outcomes. Further studies will continue to define indications for lateral versus anterior approach to lumbar spine for degenerative spondylolisthesis.

    View details for DOI 10.21037/jss.2019.05.08

    View details for PubMedID 31380471

  • Identification of the Human Skeletal Stem Cell CELL Chan, C. F., Gulati, G. S., Sinha, R., Tompkins, J., Lopez, M., Carter, A. C., Ransom, R. C., Reinisch, A., Wearda, T., Murphy, M., Brewer, R. E., Koepke, L. S., Marecic, O., Manjunath, A., Seo, E., Leavitt, T., Lu, W., Allison Nguyen, Conley, S. D., Salhotra, A., Ambrosi, T. H., Borrelli, M. R., Siebel, T., Chan, K., Schallmoser, K., Seita, J., Sahoo, D., Goodnough, H., Bishop, J., Gardner, M., Majeti, R., Wan, D. C., Goodman, S., Weissman, I. L., Chang, H. Y., Longaker, M. T. 2018; 175 (1): 43-+
  • Obesity Is Independently Associated With Early Aseptic Loosening in Primary Total Hip Arthroplasty JOURNAL OF ARTHROPLASTY Goodnough, L. H., Finlay, A. K., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2018; 33 (3): 882–86


    Obesity affects millions of patients in the United States and is associated with several complications after total hip arthroplasty (THA). The effect of obesity on the rate and mode of primary THA failure remains poorly understood, especially given other potentially confounding patient characteristics. We hypothesized that, among patients with a failed primary THA, obesity is independently associated with aseptic loosening and a higher rate of early revision.Six hundred eighty-four consecutive cases with failed THA referred to a single academic center for revision during a 10-year period were retrospectively reviewed. Multivariate logistic regression analysis was used to test the independent association between obesity and the timing as well as cause of THA failure.The rate of primary THA failure before 5 years was 48.8% in obese and 37.1% in nonobese patients (odds ratio [OR] = 1.57, P = .010). Primary THA failure before 5 years was more likely with increasing body mass index (BMI) (BMI: 35-40 kg/m2, OR = 2.31, P = .008; BMI >40 kg/m2, OR = 2.51, P = .049). The rate of primary THA failure for aseptic loosening before 5 years was 30% in obese and 18% in nonobese patients (OR = 1.88, P = .023). Obesity was not a risk for revision for infection, whereas an American Society of Anesthesiologists class ≥3 was independently associated with primary THA failure for infection (OR = 2.33, P < .001).Among patients with a failed THA, comorbidities may account for the risk of revision due to infection in obese patients. Obesity is independently associated with early primary THA failure for aseptic loosening.

    View details for DOI 10.1016/j.arth.2017.09.069

    View details for Web of Science ID 000425893000046

    View details for PubMedID 29089226

  • Antiseptics Commonly Used in Total Joint Arthroplasty Interact and May Form Toxic Products JOURNAL OF ARTHROPLASTY Campbell, S. T., Goodnough, L. H., Bennett, C. G., Giori, N. J. 2018; 33 (3): 844–46


    Multiple antiseptics have been described for use in total joint arthroplasty infection, and the use of multiple antiseptic solutions during a single operation has been described. Our clinical experience is that chlorhexidine (CHX) and Dakin's solution (NaOCl) interact and form a precipitate. The purpose of this study is to determine whether this reaction could be replicated in a laboratory setting, and to determine if other commonly used antiseptics also visibly react when mixed.Four percent chlorhexidine gluconate (CHX), 0.5% sodium hypochlorite (NaOCl), 3% hydrogen peroxide (H2O2), and 10% povidone-iodine (BTD) solutions were obtained and all possible combinations were mixed. Any visible reactions were noted and recorded, and a literature search was performed to characterize the reaction and products.CHX and NaOCl, CHX and H2O2, and CHX and BTD reacted instantly, forming a precipitate. NaOCl and H2O2 reacted to produce a gas. NaOCl and BTD reacted and produced a color change. The literature review revealed that at least 2 of the reactions tested (CHX + NaOCl and NaOCl + H2O2) could result in byproducts toxic to humans.Surgeons must be aware of these interactions when using antiseptic solutions during procedures. Caution should be used combining or mixing antiseptics, and we recommend against concomitant introduction in a surgical wound.

    View details for DOI 10.1016/j.arth.2017.10.028

    View details for Web of Science ID 000425893000039

    View details for PubMedID 29137898

  • Twist1 Contributes to Cranial Bone Initiation and Dermal Condensation by Maintaining Wnt Signaling Responsiveness DEVELOPMENTAL DYNAMICS Goodnough, L., Dinuoscio, G. J., Atit, R. P. 2016; 245 (2): 144-156


    Specification of cranial bone and dermal fibroblast progenitors in the supraorbital arch mesenchyme is Wnt/β-catenin signaling-dependent. The mechanism underlying how these cells interpret instructive signaling cues and differentiate into these two lineages is unclear. Twist1 is a target of the Wnt/β-catenin signaling pathway and is expressed in cranial bone and dermal lineages.Here, we show that onset of Twist1 expression in the mouse cranial mesenchyme is dependent on ectodermal Wnts and mesenchymal β-catenin activity. Conditional deletion of Twist1 in the supraorbital arch mesenchyme leads to cranial bone agenesis and hypoplastic dermis, as well as craniofacial malformation of eyes and palate. Twist1 is preferentially required for cranial bone lineage commitment by maintaining Wnt responsiveness. In the conditional absence of Twist1, the cranial dermis fails to condense and expand apically leading to extensive cranial dermal hypoplasia with few and undifferentiated hair follicles.Thus, Twist1, a target of canonical Wnt/β-catenin signaling, also functions to maintain Wnt responsiveness and is a key effector for cranial bone fate selection and dermal condensation.

    View details for DOI 10.1002/DVDY.24367

    View details for Web of Science ID 000368168100005

    View details for PubMedID 26677825

    View details for PubMedCentralID PMC4715624

  • Dentate Gyrus Development Requires ERK Activity to Maintain Progenitor Population and MAPK Pathway Feedback Regulation JOURNAL OF NEUROSCIENCE Vithayathil, J., Pucilowska, J., Goodnough, L., Atit, R. P., Landreth, G. E. 2015; 35 (17): 6836-6848


    The ERK/MAPK pathway is an important developmental signaling pathway. Mutations in upstream elements of this pathway result in neuro-cardio-facial cutaneous (NCFC) syndromes, which are typified by impaired neurocognitive abilities that are reliant upon hippocampal function. The role of ERK signaling during hippocampal development has not been examined and may provide critical insight into the cause of hippocampal dysfunction in NCFC syndromes. In this study, we have generated ERK1 and conditional ERK2 compound knock-out mice to determine the role of ERK signaling during development of the hippocampal dentate gyrus. We found that loss of both ERK1 and ERK2 resulted in 60% fewer granule cells and near complete absence of neural progenitor pools in the postnatal dentate gyrus. Loss of ERK1/2 impaired maintenance of neural progenitors as they migrate from the dentate ventricular zone to the dentate gyrus proper, resulting in premature depletion of neural progenitor cells beginning at E16.5, which prevented generation of granule cells later in development. Finally, loss of ERK2 alone does not impair development of the dentate gyrus as animals expressing only ERK1 developed a normal hippocampus. These findings establish that ERK signaling regulates maintenance of progenitor cells required for development of the dentate gyrus.

    View details for DOI 10.1523/JNEUROSCI.4196-14.2015

    View details for Web of Science ID 000353647600018

    View details for PubMedID 25926459

    View details for PubMedCentralID PMC4412899

  • Lack of dystrophin results in abnormal cerebral diffusion and perfusion in vivo NEUROIMAGE Goodnough, C. L., Gao, Y., Li, X., Qutaish, M. Q., Goodnough, L., Molter, J., Wilson, D., Flask, C. A., Yu, X. 2014; 102: 809-816


    Dystrophin, the main component of the dystrophin-glycoprotein complex, plays an important role in maintaining the structural integrity of cells. It is also involved in the formation of the blood-brain barrier (BBB). To elucidate the impact of dystrophin disruption in vivo, we characterized changes in cerebral perfusion and diffusion in dystrophin-deficient mice (mdx) by magnetic resonance imaging (MRI). Arterial spin labeling (ASL) and diffusion-weighted MRI (DWI) studies were performed on 2-month-old and 10-month-old mdx mice and their age-matched wild-type controls (WT). The imaging results were correlated with Evan's blue extravasation and vascular density studies. The results show that dystrophin disruption significantly decreased the mean cerebral diffusivity in both 2-month-old (7.38 ± 0.30 × 10(-4)mm(2)/s) and 10-month-old (6.93 ± 0.53 × 10(-4)mm(2)/s) mdx mice as compared to WT (8.49 ± 0.24 × 10(-4), 8.24 ± 0.25 × 10(-4)mm(2)/s, respectively). There was also an 18% decrease in cerebral perfusion in 10-month-old mdx mice as compared to WT, which was associated with enhanced arteriogenesis. The reduction in water diffusivity in mdx mice is likely due to an increase in cerebral edema or the existence of large molecules in the extracellular space from a leaky BBB. The observation of decreased perfusion in the setting of enhanced arteriogenesis may be caused by an increase of intracranial pressure from cerebral edema. This study demonstrates the defects in water handling at the BBB and consequently, abnormal perfusion associated with the absence of dystrophin.

    View details for DOI 10.1016/j.neuroimage.2014.08.053

    View details for Web of Science ID 000345391700054

    View details for PubMedID 25213753

    View details for PubMedCentralID PMC4320943

  • Distinct Requirements for Cranial Ectoderm and Mesenchyme-Derived Wnts in Specification and Differentiation of Osteoblast and Dermal Progenitors PLOS GENETICS Goodnough, L., DiNuoscio, G. J., Ferguson, J. W., Williams, T., Lang, R. A., Atit, R. P. 2014; 10 (2): e1004152


    The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule β-catenin, but the relative contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial surface ectoderm and underlying supraorbital mesenchyme during dermal and osteoblast fate selection. Using conditional genetics, we eliminate secretion of all Wnt ligands from cranial surface ectoderm or undifferentiated mesenchyme, to uncover distinct roles for ectoderm- and mesenchyme-derived Wnts. Ectoderm Wnt ligands induce osteoblast and dermal fibroblast progenitor specification while initiating expression of a subset of mesenchymal Wnts. Mesenchyme Wnt ligands are subsequently essential during differentiation of dermal and osteoblast progenitors. Finally, ectoderm-derived Wnt ligands provide an inductive cue to the cranial mesenchyme for the fate selection of dermal fibroblast and osteoblast lineages. Thus two sources of Wnt ligands perform distinct functions during osteoblast and dermal fibroblast formation.

    View details for DOI 10.1371/journal.pgen.1004152

    View details for Web of Science ID 000332021500027

    View details for PubMedID 24586192

    View details for PubMedCentralID PMC3930509

  • Twist1 mediates repression of chondrogenesis by beta-catenin to promote cranial bone progenitor specification DEVELOPMENT Goodnough, L., Chang, A. T., Treloar, C., Yang, J., Scacheri, P. C., Atit, R. P. 2012; 139 (23): 4428-4438


    The bones of the mammalian skull vault form through intramembranous ossification. Skull bones ossify directly, in a process regulated by β-catenin, instead of passing through a cartilage intermediate. We tested whether β-catenin is necessary for fate selection of intramembranous bone progenitors in the skull. Here, we show in mice that removal of β-catenin from skull bone progenitors results in the near complete transformation of the skull bones to cartilage, whereas constitutive β-catenin activation inhibits skull bone fate selection. β-catenin directly activated Twist1 expression in skull progenitors, conditional Twist1 deletion partially phenocopied the absence of β-catenin, and Twist1 deletion partially restored bone formation in the presence of constitutive β-catenin activation. Finally, Twist1 bound robustly to the 3'UTR of Sox9, the central initiator of chondrogenesis, suggesting that Twist1 might directly repress cartilage formation through Sox9. These findings provide insight into how β-catenin signaling via Twist1 actively suppresses the formation of cartilage and promotes intramembranous ossification in the skull.

    View details for DOI 10.1242/dev.081679

    View details for Web of Science ID 000310780300015

    View details for PubMedID 23095887

    View details for PubMedCentralID PMC3509735

  • Comparative gene expression analysis of avian embryonic facial structures reveals new candidates for human craniofacial disorders HUMAN MOLECULAR GENETICS Brugmann, S. A., Powder, K. E., Young, N. M., Goodnough, L. H., Hahn, S. M., James, A. W., Helms, J. A., Lovett, M. 2010; 19 (5): 920-930


    Mammals and birds have common embryological facial structures, and appear to employ the same molecular genetic developmental toolkit. We utilized natural variation found in bird beaks to investigate what genes drive vertebrate facial morphogenesis. We employed cross-species microarrays to describe the molecular genetic signatures, developmental signaling pathways and the spectrum of transcription factor (TF) gene expression changes that differ between cranial neural crest cells in the developing beaks of ducks, quails and chickens. Surprisingly, we observed that the neural crest cells established a species-specific TF gene expression profile that predates morphological differences between the species. A total of 232 genes were differentially expressed between the three species. Twenty-two of these genes, including Fgfr2, Jagged2, Msx2, Satb2 and Tgfb3, have been previously implicated in a variety of mammalian craniofacial defects. Seventy-two of the differentially expressed genes overlap with un-cloned loci for human craniofacial disorders, suggesting that our data will provide a valuable candidate gene resource for human craniofacial genetics. The most dramatic changes between species were in the Wnt signaling pathway, including a 20-fold up-regulation of Dkk2, Fzd1 and Wnt1 in the duck compared with the other two species. We functionally validated these changes by demonstrating that spatial domains of Wnt activity differ in avian beaks, and that Wnt signals regulate Bmp pathway activity and promote regional growth in facial prominences. This study is the first of its kind, extending on previous work in Darwin's finches and provides the first large-scale insights into cross-species facial morphogenesis.

    View details for DOI 10.1093/hmg/ddp559

    View details for Web of Science ID 000274341400015

    View details for PubMedID 20015954

    View details for PubMedCentralID PMC2816616

  • Wnt signaling mediates regional specification in the vertebrate face DEVELOPMENT Brugmann, S. A., Goodnough, L. H., Gregorieff, A., Leucht, P., Ten Berge, D., Fuerer, C., Clevers, H., Nusse, R., Helms, J. A. 2007; 134 (18): 3283-3295


    At early stages of development, the faces of vertebrate embryos look remarkably similar, yet within a very short timeframe they adopt species-specific facial characteristics. What are the mechanisms underlying this regional specification of the vertebrate face? Using transgenic Wnt reporter embryos we found a highly conserved pattern of Wnt responsiveness in the developing mouse face that later corresponded to derivatives of the frontonasal and maxillary prominences. We explored the consequences of disrupting Wnt signaling, first using a genetic approach. Mice carrying compound null mutations in the nuclear mediators Lef1 and Tcf4 exhibited radically altered facial features that culminated in a hyperteloric appearance and a foreshortened midface. We also used a biochemical approach to perturb Wnt signaling and found that in utero delivery of a Wnt antagonist, Dkk1, produced similar midfacial malformations. We tested the hypothesis that Wnt signaling is an evolutionarily conserved mechanism controlling facial morphogenesis by determining the pattern of Wnt responsiveness in avian faces, and then by evaluating the consequences of Wnt inhibition in the chick face. Collectively, these data elucidate a new role for Wnt signaling in regional specification of the vertebrate face, and suggest possible mechanisms whereby species-specific facial features are generated.

    View details for DOI 10.1242/dev.005132

    View details for Web of Science ID 000249013700006

    View details for PubMedID 17699607

  • Stage-dependent craniofacial defects resulting from Sprouty2 overexpression DEVELOPMENTAL DYNAMICS Goodnough, L. H., Brugmann, S. A., Hu, D., Helms, J. A. 2007; 236 (7): 1918-1928


    Sprouty genes encode intracellular regulators of receptor tyrosine kinases that function in a variety of developmental events. Although mice carrying null mutations in Sprouty genes exhibit craniofacial anomalies, the precise role of these regulatory proteins in facial development remains unclear. Here, we show that overexpression of spry2 at the initiation of craniofacial development results in a dramatic arrest in outgrowth of the facial prominences. Although endogenous spry2 and fibroblast growth factor 8 (fgf8) are coexpressed throughout much of craniofacial development, overexpression of spry2 did not alter the spatiotemporal patterns of fgf target gene expression. The morphological consequences of spry2 overexpression were specific: all of the facial prominences were truncated, but despite this gross malformation, the programs of osteogenesis and chondrogenesis were not impaired. Collectively, these data suggest that Sprouty2 plays a role in the outgrowth of facial prominences independent of canonical Fgf signaling.

    View details for DOI 10.1002/dvdy.21195

    View details for Web of Science ID 000248041000018

    View details for PubMedID 17576140