Publications by authors named "Sheldon S Lin"

56 Publications

Local insulin application has a dose-dependent effect on lumbar fusion in a rabbit model.

J Tissue Eng Regen Med 2021 Feb 19. Epub 2021 Feb 19.

Department of Orthopaedics, Rutgers-New Jersey Medical School, Newark, NJ, USA.

The purpose of this study was to determine if locally applied insulin has a dose-responsive effect on posterolateral lumbar fusion. Adult male New Zealand White rabbits underwent posterolateral intertransverse spinal fusions (PLFs) at L5-L6 using suboptimal amounts of autograft. Fusion sites were treated with collagen sponge soaked in saline (control, n = 11), or with insulin at low (5 or 10 units, n = 13), mid (20 units, n = 11), and high (40 units, n = 11) doses. Rabbits were euthanized at 6 weeks. The L5-L6 spine segment underwent manual palpation and radiographic evaluation performed by two fellowship trained spine surgeons blinded to treatment. Differences between groups were evaluated by analysis of variance on ranks followed by post-hoc Dunn's tests. Forty-three rabbits were euthanized at the planned 6 weeks endpoint, while three died or were euthanized prior to the endpoint. Radiographic evaluation found bilateral solid fusion in 10%, 31%, 60%, and 60% of the rabbits from the control and low, mid, and high-dose insulin-treated groups, respectively (p < 0.05). As per manual palpation, 7 of 10 rabbits in the mid-dose insulin group were fused as compared to 1 of 10 rabbits in the control group (p < 0.05). This study demonstrates that insulin enhanced the effectiveness of autograft to increase fusion success in the rabbit PLF model. The study indicates that insulin or insulin-mimetic compounds can be used to promote bone regeneration.
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http://dx.doi.org/10.1002/term.3182DOI Listing
February 2021

Low Intensity Pulsed Ultrasound Therapy (LIPUS): A review of evidence and potential applications in diabetics.

J Clin Orthop Trauma 2020 Jul 21;11(Suppl 4):S500-S505. Epub 2020 Apr 21.

Academic Team of Musculoskeletal Surgery, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK.

Low Intensity Pulsed Ultrasound Therapy (LIPUS) is a non-invasive treatment and aims to reduce fracture healing time and avoid non-union by delivering micro-mechanical stress to the bone to stimulate bone healing. In 2018, the National Institute for Health and Clinical Excellence (NICE) recommended that the evidence for LIPUS to promote healing of delayed-union and non-union fractures raised no major safety concerns, but the current evidence on efficacy is inadequate in quality. Little is known about the potential benefits of LIPUS for fracture healing in diabetic patients. In this article, we review the current evidence of LIPUS therapy both in animal and human studies and its possible application on fractures in diabetics.
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http://dx.doi.org/10.1016/j.jcot.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394837PMC
July 2020

Zinc as a Therapeutic Agent in Bone Regeneration.

Materials (Basel) 2020 May 12;13(10). Epub 2020 May 12.

Department of Biological Sciences, Seton Hall University, 400 South Orange Avenue, South Orange, NJ 07079, USA.

Zinc is an essential mineral that is required for normal skeletal growth and bone homeostasis. Furthermore, zinc appears to be able to promote bone regeneration. However, the cellular and molecular pathways through which zinc promotes bone growth, homeostasis, and regeneration are poorly understood. Zinc can positively affect chondrocyte and osteoblast functions, while inhibiting osteoclast activity, consistent with a beneficial role for zinc in bone homeostasis and regeneration. Based on the effects of zinc on skeletal cell populations and the role of zinc in skeletal growth, therapeutic approaches using zinc to improve bone regeneration are being developed. This review focuses on the role of zinc in bone growth, homeostasis, and regeneration while providing an overview of the existing studies that use zinc as a bone regeneration therapeutic.
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http://dx.doi.org/10.3390/ma13102211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287917PMC
May 2020

President and Program Chair's Introduction.

Foot Ankle Int 2018 09;39(2_suppl):75S

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http://dx.doi.org/10.1177/1071100718792905DOI Listing
September 2018

Medical Malpractice in Orthopedic Surgery: A Westlaw-Based Demographic Analysis.

Orthopedics 2018 Sep 26;41(5):e615-e620. Epub 2018 Jun 26.

A recent study that evaluated the risk of facing a malpractice claim by physician specialty found that orthopedic surgeons were at a significantly greater risk of being sued than other medical specialists. To date, no studies have characterized trends in orthopedic surgery malpractice claims. The Westlaw legal database was used to locate state and federal jury verdicts and settlements related to medical malpractice and orthopedic surgery from 2010 to 2016. Eighty-one cases were analyzed. The mean age of the affected patients and/or plaintiffs was 53.4 years. Spine surgery (21 cases; 25.9%), knee surgery (17 cases; 21.0%), and hip surgery (11 cases; 13.6%) were litigated most often. Procedural error (71 cases; 87.7%) and negligence (58 cases; 71.6%) were the 2 most commonly cited reasons for litigation. The jury found in favor of the defendant in most (50 cases; 61.7%) of the cases. The mean plaintiff (17 cases; 21.0%) verdict payout was $3,015,872, and the mean settlement (13 cases; 16.0%) value was $1,570,833. Unnecessary surgery (odds ratio [OR], 12.29; 95% confidence interval [CI], 1.91-108.46; P=.040) and surgery resulting in death (OR, 26.26; 95% CI, 2.55-497.42; P=.040) were significant predictors of a verdict in favor of the plaintiff. Patient death (OR, 0.05; 95% CI, 0.01-0.38; P=.021) and male patient sex (OR, 0.26; 95% CI, 0.09-0.71; P=.033) were significant negative predictors of a verdict in favor of the defendant. The jury found in favor of the defendant orthopedic surgeon in most cases. Procedural error and/or negligence were cited most commonly by the plaintiffs as the bases for the claims. Verdicts in favor of the plaintiffs resulted in payouts nearly double those of settlements. [Orthopedics. 2018; 41(5):e615-e620.].
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http://dx.doi.org/10.3928/01477447-20180621-06DOI Listing
September 2018

What's New in Foot and Ankle Surgery.

J Bone Joint Surg Am 2018 May;100(10):892-898

Department of Orthopaedics, Rutgers New Jersey School of Medicine, Newark, New Jersey.

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http://dx.doi.org/10.2106/JBJS.17.01672DOI Listing
May 2018

What's New in Foot and Ankle Surgery.

J Bone Joint Surg Am 2017 04;99(8):700-706

1Department of Orthopaedics, New Jersey Medical School, Newark, New Jersey.

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http://dx.doi.org/10.2106/JBJS.16.01603DOI Listing
April 2017

Biologics Fusion.

Foot Ankle Spec 2017 Feb;10(1):43-45

Assistant Professor of Orthopaedic Surgery Foot and Ankle Fellowship Director University of Virginia Charlottesville, VA.

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http://dx.doi.org/10.1177/1938640016689170DOI Listing
February 2017

Effects of local vanadium delivery on diabetic fracture healing.

J Orthop Res 2017 10 8;35(10):2174-2180. Epub 2017 Mar 8.

Department of Orthopaedics, Rutgers New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07101.

This study evaluated the effect of local vanadyl acetylacetonate (VAC), an insulin mimetic agent, upon the early and late parameters of fracture healing in rats using a standard femur fracture model. Mechanical testing, and radiographic scoring were performed, as well as histomorphometry, including percent bone, percent cartilage, and osteoclast numbers. Fractures treated with local 1.5 mg/kg VAC possessed significantly increased mechanical properties compared to controls at 6 weeks post-fracture, including increased torque to failure (15%; p = 0.046), shear modulus (89%; p = 0.043), and shear stress (81%; p = 0.009). The radiographic scoring analysis showed increased cortical bridging at 4 weeks and 6 weeks (119%; p = 0.036 and 209%; p = 0.002) in 1.5 mg/kg VAC treated groups. Histomorphometry of the fracture callus at days 10 and 14 showed increased percent cartilage (121%; p = 0.009 and 45%; p = 0.035) and percent mineralized tissue (66%; p = 0.035 and 58%; p = 0.006) with local VAC treated groups compared to control. Additionally, fewer osteoclasts were observed in the local VAC treated animals as compared to controls at day 14 (0.45% ± 0.29% vs. 0.83% ± 0.36% of callus area; p = 0.032). The results suggest local administration of VAC acts to modulate osteoclast activity and increase percentage of early callus cartilage, ultimately enhancing mechanical properties comparably to non-diabetic animals treated with local VAC. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2174-2180, 2017.
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http://dx.doi.org/10.1002/jor.23521DOI Listing
October 2017

Local Zinc Chloride Release From a Calcium Sulfate Carrier Enhances Fracture Healing.

J Orthop Trauma 2017 Mar;31(3):168-174

*Department of Orthopaedics, Rutgers New Jersey Medical School, Newark, NJ; †Department of Biological Sciences, Seton Hall University, South Orange, NJ; and ‡Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, NJ.

Background: This study examined the efficacy of calcium sulfate (CaSO4) as a carrier for intramedullary delivery of zinc chloride (ZnCl2) to treat fracture healing in a BB Wistar rat model. A non-carrier-mediated injection of 3.0 mg/kg of ZnCl2 has previously been shown to enhance fracture healing.

Methods: A heterogeneous mixture of ZnCl2 and CaSO4 was administered into the intramedullary femoral canal and a mid-diaphyseal femur fracture was created unilaterally. Early and late parameters of fracture healing were assessed using biomechanical testing, radiographic scoring, quantitative histomorphometry (for percentage of new cartilage and bone within the fracture callus), and long-term histologic evaluation.

Results: Fractures treated with 1.0 mg/kg of ZnCl2/CaSO4 demonstrated a significantly higher maximum torque to failure compared with both CaSO4 (P = 0.048) and saline (P = 0.005) controls at 4 weeks postfracture (396.4 versus 251.3 versus 178.7 N mm, respectively). Statistically significant increases in torsional rigidity, effective shear modulus, and effective shear stress were also found, as well as a 3.5 times increase in radiographic score (based on bone union). Histologic examination of the fracture callus indicated enhanced chondrogenesis at day 14 postfracture, with increased percent cartilage for the ZnCl2/CaSO4 group compared with saline (P = 0.0004) and CaSO4 (P = 0.0453) controls. Long-term radiographic and histologic evaluation revealed no abnormal bone formation or infection up to 12 weeks postoperatively.

Conclusions: The effective dose of ZnCl2 augmentation for the enhancement of fracture healing in rats was reduced 3-fold in this study compared with previous findings. Furthermore, CaSO4 acted synergistically with ZnCl2 to increase the mechanical strength and stability at the fracture site.
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http://dx.doi.org/10.1097/BOT.0000000000000748DOI Listing
March 2017

Orthobiologic in Foot Ankle.

Authors:
Sheldon S Lin

Foot Ankle Clin 2016 Dec;21(4):xiii-xiv

Rutgers New Jersey Medical School, Department of Orthopaedics, Suite 7300, Doctor's Office Center, 90 Bergen Street, Newark, NJ 07101-1709, USA. Electronic address:

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http://dx.doi.org/10.1016/j.fcl.2016.09.001DOI Listing
December 2016

The Role of Orthobiologics in Fracture Healing and Arthrodesis.

Foot Ankle Clin 2016 Dec;21(4):727-737

Department of Orthopaedics, Rutgers New Jersey Medical School, 140 Bergen Street, ACC Building, Suite D-1610, Newark, NJ 07103, USA.

Nonunion after tibial shaft fracture and hindfoot arthrodesis remains a major problem. Known risk factors include advanced age, immunosuppression, smoking, and diabetes. Several factors must be considered in the fracture healing process. This review evaluates the efficacy of orthobiologics in improving union rates after fracture or arthrodesis. Use of compounds have shown increased cellular proliferation experimentally. Percutaneous autologous bone marrow has shown increased cellular proliferation. Matrix supplementation has shown significant improvements in bone healing. Several studies have highlighted the importance of adequate graft fill over graft type. Patients at increased risk for nonunion would benefit most from these adjuvant therapies.
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http://dx.doi.org/10.1016/j.fcl.2016.07.003DOI Listing
December 2016

The Importance of Sufficient Graft Material in Achieving Foot or Ankle Fusion.

J Bone Joint Surg Am 2016 Aug;98(15):1260-7

Department of Orthopaedics, University of Rochester School of Medicine and Dentistry, Rochester, New York.

Background: Nonunion, an important complication following foot and ankle arthrodesis, causes substantial morbidity and disability. In patients undergoing hindfoot and ankle arthrodesis, autogenous bone graft (autograft) or a suitable alternative is often used to promote osseous fusion across the joint. This study assessed the importance of adequate graft material in the fusion space to achieve joint fusion during ankle and hindfoot arthrodesis.

Methods: This study used data from a previously published clinical trial of grafting material (recombinant human platelet-derived growth factor-BB with beta-tricalcium phosphate [rhPDGF-BB/β-TCP] or autograft) for healing in hindfoot and ankle arthrodesis to correlate the amount of graft fill at 9 weeks with ultimate healing. Patients who received supplemental graft material for ankle or hindfoot arthrodesis for end-stage ankle or hindfoot arthritis were stratified according to nonunion risk factors and surgical fusion site. Patients underwent arthrodesis using standard rigid internal fixation. Graft fill was defined as "adequate" if the material occupied ≥50% of the cross-sectional area of the fusion space on a computed tomography (CT) scan made at 9 weeks. Fusion was defined as osseous bridging of ≥50% of each articulation on a CT scan made at 24 weeks. Three hundred and seventy-nine patients with 573 joints (383 managed with rhPDGF-BB/β-TCP and 190 managed with autograft) that underwent arthrodesis had complete follow-up with 9-week and 24-week CT scans available.

Results: Overall, 472 (82%) of 573 joints had adequate graft fill; of those, 383 (81%) were successfully fused at 24 weeks compared with 21 (21%) of 101 joints without adequate graft fill (p < 0.0001). Absolute fusion rate differences (joints with adequate fill minus those without adequate fill) were consistent across joints (61% to 63%) and for graft materials. The overall odds ratio (OR) of successful fusion in joints with adequate graft fill compared with those without adequate graft fill was 16.4 (95% confidence interval, 9.6 to 27.9).

Conclusions: This study demonstrates an association between the amount of graft material and successful hindfoot and ankle arthrodesis. Graft material filling of ≥50% of the fusion space at 9 weeks, regardless of type or origin, was associated with significantly higher fusion rates at 24 weeks.

Level Of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.15.00879DOI Listing
August 2016

What's New in Foot and Ankle Surgery.

J Bone Joint Surg Am 2016 May;98(10):874-80

Department of Orthopaedics, New Jersey Medical School, Rutgers University, Newark, New Jersey.

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http://dx.doi.org/10.2106/JBJS.16.00001DOI Listing
May 2016

Zinc has insulin-mimetic properties which enhance spinal fusion in a rat model.

Spine J 2016 06 2;16(6):777-83. Epub 2016 Feb 2.

Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA.

Background Context: Previous studies have found that insulin or insulin-like growth factor treatment can stimulate fracture healing in diabetic and normal animal models, and increase fusion rates in a rat spinal fusion model. Insulin-mimetic agents, such as zinc, have demonstrated antidiabetic effects in animal and human studies, and these agents that mimic the effects of insulin could produce the same beneficial effects on bone regeneration and spinal fusion.

Purpose: The purpose of this study was to analyze the effects of locally applied zinc on spinal fusion in a rat model.

Study Design/setting: Institutional Animal Care and Use Committee-approved animal study using Sprague-Dawley rats was used as the study design.

Methods: Thirty Sprague-Dawley rats (450-500 g) underwent L4-L5 posterolateral lumbar fusion (PLF). After decortication and application of approximately 0.3 g of autograft per side, one of three pellets were added to each site: high-dose zinc calcium sulfate (ZnCaSO4), low-dose ZnCaSO4 (half of the high dose), or a control palmitic acid pellet (no Zn dose). Systemic blood glucose levels were measured 24 hours postoperatively. Rats were sacrificed after 8weeks and the PLFs analyzed qualitatively by manual palpation and radiograph review, and quantitatively by micro-computed tomography (CT) analysis of bone volume and trabecular thickness. Statistical analyses with p-values set at .05 were accomplished with analysis of variance, followed by posthoc tests for quantitative data, or Mann-Whitney rank tests for qualitative assessments.

Results: Compared with controls, the low-dose zinc group demonstrated a significantly higher manual palpation grade (p=.011), radiographic score (p=.045), and bone formation on micro-CT (172.9 mm(3) vs. 126.7 mm(3) for controls) (p<.01). The high-dose zinc also demonstrated a significantly higher radiographic score (p=.017) and bone formation on micro-CT (172.7 mm(3) vs. 126.7 mm(3)) (p<.01) versus controls, and was trending toward higher manual palpation scores (p=.058).

Conclusions: This study demonstrates the potential benefit of a locally applied insulin-mimetic agent, such as zinc, in a rat lumbar fusion model. Previous studies have demonstrated the benefits of local insulin application in the same model, and it appears that zinc has similar effects.
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http://dx.doi.org/10.1016/j.spinee.2016.01.190DOI Listing
June 2016

Orthobiologics in Foot and Ankle Surgery.

J Am Acad Orthop Surg 2016 Feb;24(2):113-22

From Rutgers New Jersey Medical School, Department of Orthopedics, Newark, NJ.

Exploration into the molecular aspects of the healing process has led to the development of autologous and recombinant biologic agents. These products, collectively known as orthobiologics, have the potential to optimize favorable outcomes with respect to bone and soft-tissue restoration and to maximize the natural healing response. These orthobiologics include platelet-derived growth factor, bone morphogenetic proteins, and platelet-rich plasma. Although the usefulness of these growth factors is well described in various fields of surgery, few data exist to support or oppose the specific application of growth factors in foot and ankle surgery.
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http://dx.doi.org/10.5435/JAAOS-D-14-00155DOI Listing
February 2016

Polymerase Chain Reaction molecular diagnostic technology for monitoring chronic osteomyelitis.

J Exp Orthop 2014 Dec 15;1(1). Epub 2014 Aug 15.

Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

Background: Osteomyelitis is a devastating condition whose treatment relies on the detection of bacteria. The current standard of microbiology culture may not be adequate. Molecular biology based diagnostic procedures for detecting bacteria in orthopaedic infections was previously established, but has not been applied to the setting of chronic osteomyelitis. We aim to determine the applicability of molecular diagnostic procedures for monitoring chronic osteomyelitis, and to evaluate if these procedures are superior to standard culture methods of osteomyelitis detection.

Methods: A rabbit experimental model of chronic osteomyelitis was used; infection was induced in the proximal, medial aspect of the tibia with Staphylococcus aureus at titers ranging from 1 × 10(2) to 1 × 10(6) colony forming units. At 28 days post-infection, animals were sacrificed, and the tibias were examined radiographically, harvested, and assayed for the presence of bacteria. Two bacterial detection methods were used: (1) standard microbiological culturing, and (2) polymerase chain reaction (PCR) based diagnostic method to detect bacterial genomic DNA.

Results: The molecular diagnostic method was highly sensitive and accurate, and detected low titer infections that were undetected by radiographic and microbiological methods. By using two sets of PCR primers, one for a universal bacterial gene (16S rRNA) and one for a species-specific gene (nuc), the molecular protocol allowed both the detection and speciation of the bacterial infection.

Conclusions: The use of the PCR-based method was effective for high-sensitivity detection and identification of bacteria associated with chronic osteomyelitis in a rabbit model. Our findings illustrate the applicability of PCR for monitoring chronic osteomyelitis, which may be useful for improved detection of osteomyelitis organisms in humans.
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http://dx.doi.org/10.1186/s40634-014-0009-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648848PMC
December 2014

A not-so-systematic review.

Can J Surg 2014 Oct;57(5):E150-1

Project Professor, Division of Molecular and Cellular Biology of Mineralized Tissues, Department of Oral Sciences, Kanagawa Dental University, Graduate School of Dentistry, Yokosuka, Japan.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183692PMC
http://dx.doi.org/10.1503/cjs.009514DOI Listing
October 2014

Local manganese chloride treatment accelerates fracture healing in a rat model.

J Orthop Res 2015 Jan 17;33(1):122-30. Epub 2014 Sep 17.

Department of Orthopaedics, Rutgers-New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey, 07103.

This study investigated the effects of local delivery of manganese chloride (MnCl2), an insulin-mimetic compound, upon fracture healing using a rat femoral fracture model. Mechanical testing, histomorphometry, and immunohistochemistry were performed to assess early and late parameters of fracture healing. At 4 weeks post-fracture, maximum torque to failure was 70% higher (P<0.05) and maximum torsional rigidity increased 133% (P<0.05) in animals treated with 0.125 mg/kg MnCl2 compared to saline controls. Histological analysis of the fracture callus revealed percent new mineralized tissue was 17% higher (P<0.05) at day 10. Immunohistochemical analysis of the 0.125 mg/kg MnCl2 treated group, compared to saline controls, showed a 379% increase in the density of VEGF-C+ cells. In addition, compared to saline controls, the 0.125 mg/kg MnCl2 treated group showed a 233% and 150% increase in blood vessel density in the subperiosteal region at day 10 post-fracture as assessed by detection of PECAM and smooth muscle α actin, respectively. The results suggest that local MnCl2 treatment accelerates fracture healing by increasing mechanical parameters via a potential mechanism of amplified early angiogenesis leading to increased osteogenesis. Therefore, local administration of MnCl2 is a potential therapeutic adjunct for fracture healing.
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http://dx.doi.org/10.1002/jor.22733DOI Listing
January 2015

Local ZnCl2 accelerates fracture healing.

J Orthop Res 2014 Jun 26;32(6):834-41. Epub 2014 Feb 26.

Rutgers New Jersey Medical School, Department of Orthopaedics, 90 Bergen Street, Suite 7300, Newark, New Jersey, 07103.

This study evaluated the effect of local zinc chloride (ZnCl2 ), an insulin mimetic agent, upon the early and late parameters of fracture healing in rats using a standard femur fracture model. Mechanical testing, radiographic scoring, histomorphometry, qualitative histological scoring, PCNA immunohistochemistry, and local growth factor analysis were performed. Fractures treated with local ZnCl2 possessed significantly increased mechanical properties compared to controls at 4 weeks post fracture. The radiographic scoring analysis showed increased cortical bridging at 4 weeks in the 1.0 (p=0.0015) and 3.0 (p<0.0001) mg/kg ZnCl2 treated groups. Histomorphometry of the fracture callus at day 7 showed 177% increase (p=0.036) in percent cartilage and 133% increase (p=0.002) in percent mineralized tissue with local ZnCl2 treatment compared to controls. Qualitative histological scoring showed a 2.1× higher value at day 7 in the ZnCl2 treated group compared to control (p = 0.004). Cell proliferation and growth factors, VEGF and IGF-I, within fracture calluses treated with local ZnCl2 were increased at day 7. The results suggest local administration of ZnCl2 increases cell proliferation, causing increased growth factor production which yields improved chondrogenesis and endochondral ossification. Ultimately, these events lead to accelerated fracture healing as early as 4 weeks post fracture.
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http://dx.doi.org/10.1002/jor.22593DOI Listing
June 2014

Local vanadium release from a calcium sulfate carrier accelerates fracture healing.

J Orthop Res 2014 May 30;32(5):727-34. Epub 2013 Dec 30.

Department of Orthopaedics, Rutgers New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey, 07103.

This study evaluated the efficacy of using calcium sulfate (CaSO4 ) as a carrier for intramedullary delivery of an organic vanadium salt, vanadyl acetylacetonate (VAC) after femoral fracture. VAC can act as an insulin-mimetic and can be used to accelerate fracture healing in rats. A heterogenous mixture of VAC and CaSO4 was delivered to the fracture site of BB Wistar rats, and mechanical testing, histomorphometry, micro-computed tomography (micro-CT) were performed to measure healing. At 4 weeks after fracture, maximum torque to failure, effective shear modulus, and effective shear stress were all significantly higher (p < 0.05) in rats treated with 0.25 mg/kg VAC-CaSO4 as compared to carrier control rats. Histomorphometry found a 71% increase in percent cartilage matrix (p < 0.05) and a 64% decrease in percent mineralized tissue (p < 0.05) at 2 weeks after fracture in rats treated with 0.25 mg/kg of VAC-CaSO4 . Micro-CT analyses at 4 weeks found a more organized callus structure and higher trending maximum connected z-ray. fraction for VAC-CaSO4 groups. Evaluation of radiographs and serial histological sections at 12 weeks did not show any evidence of ectopic bone formation. As compared to previous studies, CaSO4 was an effective carrier for reducing the dose of VAC required to accelerate femoral fracture healing in rats.
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http://dx.doi.org/10.1002/jor.22570DOI Listing
May 2014

Survey on the need for bone graft in foot and ankle fusion surgery.

Foot Ankle Int 2013 Dec 28;34(12):1629-33. Epub 2013 Aug 28.

University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

Background: Generally, autologous bone graft is felt to be an important treatment adjunct in the presence of structural deformity, surface irregularities, defects (due to trauma, surgery, or degenerative changes), or underlying comorbidities that predispose the patient to healing challenges. This study assessed the prognostic and predictive factors used in the clinical decision making for bone graft supplementation in foot and ankle fusion surgery.

Methods: Utilizing standard survey research methodology, key-informant interviews, pretesting, and pilot testing; a survey was constructed. The survey consisted of a web-based 5-point Likert-type scale (never, seldom, sometimes, almost always, always) listing 14 clinical and 11 radiologic criteria that may influence the use of autologous bone grafting or other biologic augmentation in foot and ankle surgery. This survey was sent to Orthopaedic Foot and Ankle Surgeons in North America and Canada.

Results: A total of 48 foot and ankle surgeons completed the blinded survey (73% response rate). More than 70% of responders felt bone graft was almost always (AA) or always (A) indicated in prior nonunion of the indicated joint (96%). Fewer than 50% of respondents felt poor soft tissue integrity (20%), prior foot and ankle infection (20%), and current foot and ankle infection (4%) needed bone graft. Radiologic factors marked as AA or A in over 70% of responders include radiographic evidence of nonunion (96%), avascular necrosis (87%), and others. Factors chosen as AA or A by fewer than 50% of surgeons include prior adjacent joint fusions (47%), intra-articular deformity (31%), and extra-articular deformity (13%).

Conclusions: There was some uniformity of agreement on the number of both clinical and radiologic factors that prompt a surgeon to utilize autologous bone graft to try to avoid the complication of nonunion. Surgeons may wish to consider these factors when making a decision on the use of bone graft to supplement fusion.
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http://dx.doi.org/10.1177/1071100713503815DOI Listing
December 2013

Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/β-TCP): an alternative to autogenous bone graft.

J Bone Joint Surg Am 2013 Jul;95(13):1184-92

Department of Orthopaedic Surgery, The Warren Alpert School of Medicine at Brown University, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.

Background: Joint arthrodesis employing autogenous bone graft (autograft) remains a mainstay in the treatment of many foot and ankle problems. However, graft harvest can lead to perioperative morbidity and increased cost. We tested the hypothesis that purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) homodimer combined with an osteoconductive matrix (beta-tricalcium phosphate [β-TCP]) would be a safe and effective alternative to autograft.

Methods: A total of 434 patients were enrolled in thirty-seven clinical sites across North America in a prospective, randomized (2:1), controlled, non-inferiority clinical trial to compare the safety and efficacy of the combination rhPDGF-BB and β-TCP with those of autograft in patients requiring hindfoot or ankle arthrodesis. Radiographic, clinical, functional, and quality-of-life end points were assessed through fifty-two weeks postoperatively.

Results: Two hundred and sixty patients (394 joints) underwent arthrodesis with use of rhPDGF-BB/β-TCP. One hundred and thirty-seven patients (203 joints) underwent arthrodesis with use of autograft. With regard to the primary end point, 159 patients (61.2% [262 joints (66.5%)]) in the rhPDGF-BB/β-TCP group and eighty-five patients (62.0% [127 joints (62.6%)]) in the autograft group were fused as determined by computed tomography at six months (p < 0.05). Clinically, 224 patients (86.2%) [348 joints (88.3%)]) in the rhPDGF-BB/β-TCP group were considered healed at fifty-two weeks, compared with 120 patients (87.6% [177 joints (87.2%)] in the autograft group (p = 0.008). Overall, fourteen of sixteen secondary end points at twenty-four weeks and fifteen of sixteen secondary end points at fifty-two weeks demonstrated statistical non-inferiority between the groups, and patients in the rhPDGF-BB/β-TCP group were found to have less pain and an improved safety profile.

Conclusions: In patients requiring hindfoot or ankle arthrodesis, treatment with rhPDGF-BB/β-TCP resulted in comparable fusion rates, less pain, and fewer side effects as compared with treatment with autograft.
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http://dx.doi.org/10.2106/JBJS.K.01422DOI Listing
July 2013

The effects of local insulin application to lumbar spinal fusions in a rat model.

Spine J 2013 Jan 5;13(1):22-31. Epub 2013 Jan 5.

Department of Orthopaedics, UMDNJ-New Jersey Medical School, 90 Bergen St, DOC 7300, Newark, NJ 07101, USA.

Background Context: The rates of pseudoarthrosis after a single-level spinal fusion have been reported up to 35%, and the agents that increase the rate of fusion have an important role in decreasing pseudoarthrosis after spinal fusion. Previous studies have analyzed the effects of local insulin application to an autograft in a rat segmental defect model. Defects treated with a time-released insulin implant had significantly more new bone formation and greater quality of bone compared with controls based on histology and histomorphometry. A time-released insulin implant may have similar effects when applied in a lumbar spinal fusion model.

Purpose: This study analyzes the effects of a local time-released insulin implant applied to the fusion bed in a rat posterolateral lumbar spinal fusion model. Our hypothesis was twofold: first, a time-released insulin implant applied to the autograft bed in a rat posterolateral lumbar fusion will increase the rate of successful fusion and second, will alter the local environment of the fusion site by increasing the levels of local growth factors.

Study Design: Animal model (Institutional Animal Care and Use Committee approved) using 40 adult male Sprague-Dawley rats.

Methods: Forty skeletally mature Sprague-Dawley rats weighing approximately 500 g each underwent posterolateral intertransverse lumbar fusions with iliac crest autograft from L4 to L5 using a Wiltse-type approach. After exposure of the transverse processes and high-speed burr decortication, a Linplant (Linshin Canada, Inc., ON, Canada) consisting of 95% microrecrystalized palmitic acid and 5% bovine insulin (experimental group) or a sham implant consisting of only palmitic acid (control group) was implanted on the fusion bed with iliac crest autograft. As per the manufacturer, the Linplant has a release rate of 2 U/day for a minimum of 40 days. The transverse processes and autograft beds of 10 animals from the experimental and 10 from the control group were harvested at Day 4 and analyzed for growth factors. The remaining 20 spines were harvested at 8 weeks and underwent a radiographic examination, manual palpation, and microcomputed tomographic (micro-CT) examination.

Results: One of the 8-week control animals died on postoperative Day 1, likely due to anesthesia. In the groups sacrificed at Day 4, there was a significant increase in insulinlike growth factor-I (IGF-I) in the insulin treatment group compared with the controls (0.185 vs. 0.129; p=.001). No significant differences were demonstrated in the levels of transforming growth factor beta-1, platelet-derived growth factor-AB, and vascular endothelial growth factor between the groups (p=.461, .452, and .767 respectively). Based on the radiographs, 1 of 9 controls had a solid bilateral fusion mass, 2 of 9 had unilateral fusion mass, 3 of 9 had small fusion mass bilaterally, and 3 of 9 had graft resorption. The treatment group had solid bilateral fusion mass in 6 of 10 and unilateral fusion mass in 4 of 10, whereas a small bilateral fusion mass and graft resorption were not observed. The difference between the groups was significant (p=.0067). Based on manual palpation, only 1 of 9 controls was considered fused, 4 of 9 were partially fused, and 4 of 9 were not fused. In the treatment group, there were 6 of 10 fusions, 3 of 10 partial fusions, and 1 of 10 were not fused. The difference between the groups was significant (p=.0084). Based on the micro-CT, the mean bone volume of the control group was 126.7 mm(3) and 203.8 mm(3) in the insulin treatment group. The difference between the groups was significant (p=.0007).

Conclusions: This study demonstrates the potential role of a time-released insulin implant as a bone graft enhancer using a rat posterolateral intertransverse lumbar fusion model. The insulin-treatment group had significantly higher fusion rates based on the radiographs and manual palpation and had significantly higher levels of IGF-I and significantly more bone volume on micro-CT.
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http://dx.doi.org/10.1016/j.spinee.2012.11.030DOI Listing
January 2013

Effects of local insulin delivery on subperiosteal angiogenesis and mineralized tissue formation during fracture healing.

J Orthop Res 2013 May 13;31(5):783-91. Epub 2012 Dec 13.

Department of Orthopaedics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, NJ 07103, USA.

Local insulin delivery has been shown to improve osseous healing in diabetic animals. The purpose of this study was to quantify the effects of local intramedullary delivery of saline or Ultralente insulin (UL) on various fracture healing parameters using an in vivo non-diabetic BB Wistar rat model. Quantitation of local insulin levels showed a rapid release of insulin from the fractured femora, demonstrating complete release at 2 days. RT-PCR analysis revealed that the expression of early osteogenic markers (Col1α2, osteopontin) was significantly enhanced with UL treatment when compared with saline controls (p < 0.05). Significant differences in VEGF + cells and vascularity were evident between the treatment and control groups at day 7 (p < 0.05). At day 21, histomorphometric analysis demonstrated a significant increase in percent mineralized tissue in the UL-treated animals compared with controls (p < 0.05), particularly within the subperiosteal region of the fracture callus. Mechanical testing at 4 weeks showed significantly greater mechanical strength for UL-treated animals (p < 0.05), but healing in control animals caught up at 6 weeks post-fracture. These results suggest that the primary osteogenic effect of UL during the early stages of fracture healing (1-3 weeks) is through an increase in osteogenic gene expression, subperiosteal angiogenesis, and mineralized tissue formation.
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http://dx.doi.org/10.1002/jor.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446235PMC
May 2013

Local insulin therapy affects fracture healing in a rat model.

J Orthop Res 2013 May 13;31(5):776-82. Epub 2012 Dec 13.

Department of Orthopaedics, University of Medicine, Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Avenue, 90 Bergen Street, Suite 7300, Newark, NJ 07103, USA.

A significant number of lower extremity fractures result in mal-union necessitating effective treatments to restore ambulation. Prior research in diabetic animal fracture models demonstrated improved healing following local insulin application to the fracture site and indicated that local insulin therapy can aid bone regeneration, at least within an insulin-dependent diabetic animal model. This study tested whether local insulin therapy could accelerate femur fracture repair in normal, non-diabetic rats. High (20 units) and low (10 units) doses of insulin were delivered in a calcium sulfate carrier which provided sustained release of the exogenous insulin for 7 days after fracture. Histomorphometry, radiographic scoring, and torsional mechanical testing were used to measure fracture healing. The fracture calluses from rats treated with high-dose insulin had significantly more cartilage than untreated rats after 7 and 14 days of healing. After 4 weeks of healing, femurs from rats treated with low-dose insulin had significantly higher radiographic scores and mechanical strength (p < 0.05), compared to the no treatment control groups. The results of this study suggest that locally delivered insulin is a potential therapeutic agent for treating bone fractures. Further studies are necessary, such as large animal proof of concepts, prior to the clinical use of insulin for bone fracture treatment.
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http://dx.doi.org/10.1002/jor.22287DOI Listing
May 2013

The effects of local vanadium treatment on angiogenesis and chondrogenesis during fracture healing.

J Orthop Res 2012 Dec 31;30(12):1971-8. Epub 2012 May 31.

Department of Orthopaedics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103, USA.

This study quantified the effects of local intramedullary delivery of an organic vanadium salt, which may act as an insulin-mimetic on fracture healing. Using a BB Wistar rat femoral fracture model, local vanadyl acetylacetonate (VAC) was delivered to the fracture site and histomorphometry, mechanical testing, and immunohistochemistry were performed. Callus percent cartilage was 200% higher at day 7 (p < 0.05) and 88% higher at day 10 (p < 0.05) in the animals treated with 1.5 mg/kg of VAC. Callus percent mineralized tissue was 37% higher at day 14 (p < 0.05) and 31% higher at day 21 (p < 0.05) in the animals treated with 1.5 mg/kg of VAC. Maximum torque to failure was 104% and 154% higher at 4 weeks post-fracture (p < 0.05) for the healing femurs from the VAC-treated (1.5 and 3.0 mg/kg) animals. Animals treated with other VAC doses demonstrated increased mechanical parameters at 4 weeks (p < 0.05). Immunohistochemistry detected 62% more proliferating cells at days 7 (p < 0.05) and 94% more at day 10 (p < 0.05) in the animals treated with 1.5 mg/kg VAC. Results showed 100% more vascular endothelial growth factor-C (VEGF-C) positive cells and 80% more blood vessels at day 7 (p < 0.05) within the callus subperiosteal region of VAC-treated animals (1.5 mg/kg) compared to controls. The results suggest that local VAC treatment affects chondrogenesis and angiogenesis within the first 7-10 days post-fracture, which leads to enhanced mineralized tissue formation and accelerated fracture repair as early as 3-4 weeks post-fracture.
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http://dx.doi.org/10.1002/jor.22159DOI Listing
December 2012

Limited evidence supports neuromuscular training for chronic lateral ankle instability.

J Bone Joint Surg Am 2012 Feb;94(4):365

The Steadman Clinic, Vail, Colorado, USA.

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http://dx.doi.org/10.2106/JBJS.9404.ebo349DOI Listing
February 2012

Prospective, randomized, multi-center feasibility trial of rhPDGF-BB versus autologous bone graft in a foot and ankle fusion model.

Foot Ankle Int 2011 Apr;32(4):344-54

University Orthopaedics, Inc., 100 Butler Dr., Providence, RI 02906, USA.

Background: The increased morbidity and surgical time associated with harvesting autologous bone graft (ABG) have encouraged surgeons to develop synthetic orthobiologic alternatives. The recombinant form of platelet-derived growth factor (rhPDGF-BB), an angiogenic, mitogenic, and chemotactic cytokine, has been shown to significantly enhance bone formation in human periodontal osseous defects when combined with a tricalcium phosphate carrier (β-TCP). The purpose of this prospective, controlled, randomized, multi-center feasibility clinical trial was to compare the safety and efficacy of this biosynthetic bone graft substitute (Augment™ Bone Graft) to ABG during ankle and hindfoot fusion.

Materials And Methods: Twenty adult subjects requiring ankle or hindfoot fusion from three U.S. centers were enrolled and randomized in a 2:1 ratio to receive Augment™ or ABG, respectively. Surgical approach and fixation techniques were standardized, and minimum followup was 9 months. The primary endpoint was radiographic osseous union, evaluated by a blinded independent radiologist. Secondary endpoints included assessment of clinical success, union rate by serial computed tomography (CT) examination, time to full weightbearing, AOFAS Ankle-Hindfoot Score (AOFAS), Foot Function Index (FFI), Short Form-12 (SF-12), and Visual Analog pain assessment Scale (Pain VAS).

Results: At 36 weeks, 77% (10/13) of the Augment™ and 50% (3/6) of the ABG patients were fused based on radiographic criteria. There were two nonunions in the Augment™ group (9%, 2/14). Healing rates based on 12 week CT scanning (50% osseous bridging) were 69% (9/13) in the Augment™ and 60% (3/5) in the ABG groups, respectively. All functional outcome measures (FFI, AOFAS, SF-12), as well as the VAS pain scores, improved in both groups over time. Surgical procedure times lasted an average 26 minutes longer for the ABG as compared to the Augment™ populations. There were no device related serious adverse events in this study.

Conclusion: Based on the available data, the rate of radiographic union, time to full weightbearing, and outcomes scores between the Augment™ and ABG subjects appear comparable. Augment™ may represent a safe and efficacious treatment alternative to ABG during foot and ankle arthrodesis.
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http://dx.doi.org/10.3113/FAI.2011.0344DOI Listing
April 2011