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Bone & Joint Research
Vol. 13, Issue 9 | Pages 462 - 473
6 Sep 2024
Murayama M Chow SK Lee ML Young B Ergul YS Shinohara I Susuki Y Toya M Gao Q Goodman SB

Bone regeneration and repair are crucial to ambulation and quality of life. Factors such as poor general health, serious medical comorbidities, chronic inflammation, and ageing can lead to delayed healing and nonunion of fractures, and persistent bone defects. Bioengineering strategies to heal bone often involve grafting of autologous bone marrow aspirate concentrate (BMAC) or mesenchymal stem cells (MSCs) with biocompatible scaffolds. While BMAC shows promise, variability in its efficacy exists due to discrepancies in MSC concentration and robustness, and immune cell composition. Understanding the mechanisms by which macrophages and lymphocytes – the main cellular components in BMAC – interact with MSCs could suggest novel strategies to enhance bone healing. Macrophages are polarized into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, and influence cell metabolism and tissue regeneration via the secretion of cytokines and other factors. T cells, especially helper T1 (Th1) and Th17, promote inflammation and osteoclastogenesis, whereas Th2 and regulatory T (Treg) cells have anti-inflammatory pro-reconstructive effects, thereby supporting osteogenesis. Crosstalk among macrophages, T cells, and MSCs affects the bone microenvironment and regulates the local immune response. Manipulating the proportion and interactions of these cells presents an opportunity to alter the local regenerative capacity of bone, which potentially could enhance clinical outcomes.

Cite this article: Bone Joint Res 2024;13(9):462–473.


The Bone & Joint Journal
Vol. 106-B, Issue 5 Supple B | Pages 105 - 111
1 May 2024
Apinyankul R Hong C Hwang KL Burket Koltsov JC Amanatullah DF Huddleston JI Maloney WJ Goodman SB

Aims

Instability is a common indication for revision total hip arthroplasty (THA). However, even after the initial revision, some patients continue to have recurrent dislocation. The aim of this study was to assess the risk for recurrent dislocation after revision THA for instability.

Methods

Between 2009 and 2019, 163 patients underwent revision THA for instability at Stanford University Medical Center. Of these, 33 (20.2%) required re-revision due to recurrent dislocation. Cox proportional hazard models, with death and re-revision surgery for periprosthetic infection as competing events, were used to analyze the risk factors, including the size and alignment of the components. Paired t-tests or Wilcoxon signed-rank tests were used to assess the outcome using the Veterans RAND 12 (VR-12) physical and VR-12 mental scores, the Harris Hip Score (HHS) pain and function, and the Hip disability and Osteoarthritis Outcome score for Joint Replacement (HOOS, JR).


Bone & Joint Research
Vol. 13, Issue 1 | Pages 28 - 39
10 Jan 2024
Toya M Kushioka J Shen H Utsunomiya T Hirata H Tsubosaka M Gao Q Chow SK Zhang N Goodman SB

Aims

Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice.

Methods

We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR).


The Bone & Joint Journal
Vol. 102-B, Issue 5 | Pages 593 - 599
1 May 2020
Amanatullah DF Cheng RZ Huddleston III JI Maloney WJ Finlay AK Kappagoda S Suh GA Goodman SB

Aims

To establish the utility of adding the laboratory-based synovial alpha-defensin immunoassay to the traditional diagnostic work-up of a prosthetic joint infection (PJI).

Methods

A group of four physicians evaluated 158 consecutive patients who were worked up for PJI, of which 94 underwent revision arthroplasty. Each physician reviewed the diagnostic data and decided on the presence of PJI according to the 2014 Musculoskeletal Infection Society (MSIS) criteria (yes, no, or undetermined). Their initial randomized review of the available data before or after surgery was blinded to each alpha-defensin result and a subsequent randomized review was conducted with each result. Multilevel logistic regression analysis assessed the effect of having the alpha-defensin result on the ability to diagnose PJI. Alpha-defensin was correlated to the number of synovial white blood cells (WBCs) and percentage of polymorphonuclear cells (%PMN).


Bone & Joint Research
Vol. 8, Issue 10 | Pages 481 - 488
1 Oct 2019
Nathan K Lu LY Lin T Pajarinen J Jämsen E Huang J Romero-Lopez M Maruyama M Kohno Y Yao Z Goodman SB

Objectives

Up to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage–mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures.

Methods

A primary murine macrophage-MSC coculture system was used to demonstrate the optimal transition time from M1 to M2 (polarized from M1 with interleukin (IL)-4) macrophages to maximize matrix mineralization in male and female MSCs. Outcome variables included Alizarin Red staining, alkaline phosphatase (ALP) activity, and osteocalcin protein secretion.


The Bone & Joint Journal
Vol. 101-B, Issue 6_Supple_B | Pages 37 - 44
1 Jun 2019
Liu N Goodman SB Lachiewicz PF Wood KB

Aims

Patients may present with concurrent symptomatic osteoarthritis (OA) of the hip and degenerative disorders of the lumbar spine, with surgical treatment being indicated for both. Whether arthroplasty of the hip or spinal surgery should be performed first remains uncertain.

Materials and Methods

Clinical scenarios were devised for a survey asking the preferred order of surgery and the rationale for this decision for five fictional patients with both OA of the hip and degenerative lumbar disorders. These were symptomatic OA of the hip and: 1) lumbar spinal stenosis with neurological claudication; 2) lumbar degenerative spondylolisthesis with leg pain; 3) lumbar disc herniation with leg weakness; 4) lumbar scoliosis with back pain; and 5) thoracolumbar disc herniation with myelopathy. This survey was sent to 110 members of The Hip Society and 101 members of the Scoliosis Research Society. The choices of the surgeons were compared among scenarios and between surgical specialties using the chi-squared test. The free-text comments were analyzed using text-mining.


Bone & Joint Research
Vol. 8, Issue 2 | Pages 41 - 48
1 Feb 2019
Busse P Vater C Stiehler M Nowotny J Kasten P Bretschneider H Goodman SB Gelinsky M Zwingenberger S

Objectives

Intra-articular injections of local anaesthetics (LA), glucocorticoids (GC), or hyaluronic acid (HA) are used to treat osteoarthritis (OA). Contrast agents (CA) are needed to prove successful intra-articular injection or aspiration, or to visualize articular structures dynamically during fluoroscopy. Tranexamic acid (TA) is used to control haemostasis and prevent excessive intra-articular bleeding. Despite their common usage, little is known about the cytotoxicity of common drugs injected into joints. Thus, the aim of our study was to investigate the effects of LA, GC, HA, CA, and TA on the viability of primary human chondrocytes and tenocytes in vitro.

Methods

Human chondrocytes and tenocytes were cultured in a medium with three different drug dilutions (1:2; 1:10; 1:100). The following drugs were used to investigate cytotoxicity: lidocaine hydrochloride 1%; bupivacaine 0.5%; triamcinolone acetonide; dexamethasone 21-palmitate; TA; iodine contrast media; HA; and distilled water. Normal saline served as a control. After an incubation period of 24 hours, cell numbers and morphology were assessed.


The Bone & Joint Journal
Vol. 100-B, Issue 1 | Pages 28 - 32
1 Jan 2018
Goodnough LH Bala A Huddleston III JI Goodman SB Maloney WJ Amanatullah DF

Aims

Many case reports and small studies have suggested that cobalt ions are a potential cause of cardiac complications, specifically cardiomyopathy, after metal-on-metal (MoM) total hip arthroplasty (THA). The impact of metal ions on the incidence of cardiac disease after MoM THA has not been evaluated in large studies. The aim of this study was to compare the rate of onset of new cardiac symptoms in patients who have undergone MoM THA with those who have undergone metal-on-polyethylene (MoP) THA.

Patients and Methods

Data were extracted from the Standard Analytics Files database for patients who underwent MoM THA between 2005 and 2012. Bearing surface was selected using International Classification of Diseases ninth revision codes. Patients with a minimum five-year follow-up were selected. An age and gender-matched cohort of patients who underwent MoP THA served as a comparison group. New diagnoses of cardiac disease were collected during the follow-up period. Comorbidities and demographics were identified and routine descriptive statistics were used.


The Bone & Joint Journal
Vol. 99-B, Issue 10 | Pages 1267 - 1279
1 Oct 2017
Chughtai M Piuzzi NS Khlopas A Jones LC Goodman SB Mont MA

Non-traumatic osteonecrosis of the femoral head is a potentially devastating condition, the prevalence of which is increasing. Many joint-preserving forms of treatment, both medical and surgical, have been developed in an attempt to slow or reverse its progression, as it usually affects young patients.

However, it is important to evaluate the best evidence that is available for the many forms of treatment considering the variation in the demographics of the patients, the methodology and the outcomes in the studies that have been published, so that it can be used effectively.

The purpose of this review, therefore, was to provide an up-to-date, evidence-based guide to the management, both non-operative and operative, of non-traumatic osteonecrosis of the femoral head.

Cite this article: Bone Joint J 2017;99-B:1267–79.


The Bone & Joint Journal
Vol. 99-B, Issue 5 | Pages 601 - 606
1 May 2017
Narkbunnam R Amanatullah DF Electricwala AJ Huddleston III JI Maloney WJ Goodman SB

Aims

The stability of cementless acetabular components is an important factor for surgical planning in the treatment of patients with pelvic osteolysis after total hip arthroplasty (THA). However, the methods for determining the stability of the acetabular component from pre-operative radiographs remain controversial. Our aim was to develop a scoring system to help in the assessment of the stability of the acetabular component under these circumstances.

Patients and Methods

The new scoring system is based on the mechanism of failure of these components and the location of the osteolytic lesion, according to the DeLee and Charnley classification. Each zone is evaluated and scored separately. The sum of the individual scores from the three zones is reported as a total score with a maximum of 10 points. The study involved 96 revision procedures which were undertaken for wear or osteolysis in 91 patients between July 2002 and December 2012. Pre-operative anteroposterior pelvic radiographs and Judet views were reviewed. The stability of the acetabular component was confirmed intra-operatively.


The Bone & Joint Journal
Vol. 99-B, Issue 4 | Pages 440 - 444
1 Apr 2017
Lee KH Jo W Ha YC Lee YK Goodman SB Koo KH

Aims

Modular or custom-made femoral components have been preferred for total hip arthroplasty (THA) in patients with a history of Perthes’ disease because of the distortion in the anatomy of the proximal femur. However, it has not been established whether a monobloc cementless stem will fit the distorted proximal femur or whether the results of the procedure are satisfactory in this group of patients.

Patients and Methods

We reviewed 68 consecutive patients who had undergone THA for childhood Perthes’ disease between June 2003 and December 2008. There were 35 men and 33 women with a mean age of 48 years (16 to 73) at the time of index arthroplasty. Their mean body mass index was 24.4 (18.3 to 32.9). Of the 68 hips, 32 were classified as Stulberg class III and 36 as class IV. The mean pre-operative shortening of the affected leg was 17.2 mm (5 to 34). The minimum follow-up was five years (mean 8.5 years; 5.2 to 10).


The Journal of Bone & Joint Surgery British Volume
Vol. 81-B, Issue 6 | Pages 1069 - 1075
1 Nov 1999
Goodman SB Song Y Chun L Regula D Aspenberg P

We implanted bone harvest chambers (BHCs) bilaterally in ten mature male New Zealand white rabbits. Polyethylene particles (0.3 ± 0.1 −m in diameter, 6.4×1012 particles/ml) were implanted for two, four or six weeks bilaterally in the BHCs, with subsequent removal of the ingrown tissue after each treatment. In addition to the particles, one side also received 1.5 −g of recombinant transforming growth factor ß1 (TGFβ1).

At two weeks, the bone area as a percentage of total area was less in chambers containing TGFβ compared with those with particles alone (7.8 ± 1.3% v 16.9 ± 2.7% respectively; 95% confidence interval (CI) for difference -14.0 to -4.30; p = 0.002). At four weeks, the percentage area of bone was greater in chambers containing TGFβ compared with those with particles alone (31.2 ± 3.4% v 22.5 ± 2.0% respectively; 95% CI for difference 1.0 to 16.4; p = 0.03). There were no statistical differences at six weeks, despite a higher mean value with TGFβ treatment (38.2 ± 3.9% v 28.8 ± 3.5%; 95% CI for difference -4.6 to 23.3; p = 0.16). The number of vitronectin-receptor-positive cells (osteoclast-like cells) was greater in the treatment group with TGFβ compared with that with particles alone; most of these positive cells were located in the interstitium, rather than adjacent to bone.

TGFβ1 is a pleotropic growth factor which can modulate cellular events in the musculoskeletal system in a time- and concentration-dependent manner. Our data suggest that there is an early window at between two and six weeks, in which TGFβ may favourably affect bone ingrowth in the BHC model. Exogenous growth factors such as TGFβ may be a useful adjunct in obtaining osseointegration and bone ingrowth, especially in revisions when there is compromised bone stock and residual particulate debris.


The Journal of Bone & Joint Surgery British Volume
Vol. 81-B, Issue 1 | Pages 155 - 162
1 Jan 1999
Nakashima Y Sun D Trindade MCD Chun LE Song Y Goodman SB Schurman DJ Maloney WJ Smith RL

Particulate wear debris is associated with periprosthetic inflammation and loosening in total joint arthroplasty. We tested the effects of titanium alloy (Ti-alloy) and PMMA particles on monocyte/macrophage expression of the C-C chemokines, monocyte chemoattractant protein-1 (MCP-1), monocyte inflammatory protein-1 alpha (MIP-1α), and regulated upon activation normal T expressed and secreted protein (RANTES). Periprosthetic granulomatous tissue was analysed for expression of macrophage chemokines by immunohistochemistry. Chemokine expression in human monocytes/macrophages exposed to Ti-alloy and PMMA particles in vitro was determined by RT-PCR, ELISA and monocyte migration.

We observed MCP-1 and MIP-1α expression in all tissue samples from failed arthroplasties. Ti-alloy and PMMA particles increased expression of MCP-1 and MIP-1α in macrophages in vitro in a dose- and time-dependent manner whereas RANTES was not detected. mRNA signal levels for MCP-1 and MIP-1α were also observed in cells after exposure to particles. Monocyte migration was stimulated by culture medium collected from macrophages exposed to Ti-alloy and PMMA particles. Antibodies to MCP-1 and MIP-1α inhibited chemotactic activity of the culture medium samples.

Release of C-C chemokines by macrophages in response to wear particles may contribute to chronic inflammation at the bone-implant interface in total joint arthroplasty.


The Journal of Bone & Joint Surgery British Volume
Vol. 80-B, Issue 5 | Pages 924 - 930
1 Sep 1998
Lind M Trindade MCD Yaszay B Goodman SB Smith RL

The interactions between the different cell types in periprosthetic tissue are still unclear. We used a non-contact coculture model to investigate the effects of polymethylmethacrylate (PMMA) particles and human macrophage-derived soluble mediators on fibroblast activation. Macrophages were either exposed or not exposed to phagocytosable PMMA particles, but fibroblasts were not. Increasing numbers of macrophages were tested in cocultures in which the fibroblast cell number was held constant and cultures of macrophages alone were used for comparison of cytokine release. We used the release of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), lysosomal enzyme and metalloproteinase activity to assess the cultivation of macrophages and fibroblasts.

In cocultures, IL-6 release was increased 100-fold for both unchallenged and particle-challenged cultures when compared with macrophage cultures alone. Furthermore, particle-challenged cocultures had threefold higher IL-6 levels than unchallenged cocultures. Release of TNF-α was similar in cocultures and in macrophage cultures. IL-1β release in cocultures was independent of the macrophage-fibroblast ratio. Lysosomal enzyme activity and metalloproteinase activity were increased in cocultures.

Our data show that macrophages and fibroblasts in coculture significantly increase the release of IL-6 and to a less degree other inflammatory mediators; particle exposure accentuates this effect. This suggests that macrophage accumulation in fibrous tissue may lead to elevated IL-6 levels that are much higher than those caused by particle activation of macrophages alone. This macrophage-fibroblast interaction represents a novel concept for the initiation and maintenance of the inflammatory process in periprosthetic membranes.


The Journal of Bone & Joint Surgery British Volume
Vol. 80-B, Issue 4 | Pages 694 - 700
1 Jul 1998
Nakashima Y Sun D Maloney WJ Goodman SB Schurman DJ Smith RL

We exposed human macrophages isolated from the peripheral blood of healthy donors to metal and bone-cement particles from 0.2 to 10 μm in size.

Zymography showed that macrophages exposed to titanium alloy and polymethylmethacrylate (PMMA) particles released a 92- and 72-kDa gelatinase in a dose- and time-dependent manner. Western immunoblotting confirmed that the 92- and 72-kDa gelatinolytic activities corresponded to matrix metalloproteinase-9 and matrix metalloproteinase-2 (MMP-9, MMP-2), respectively. Western immunoblotting also indicated that titanium alloy and PMMA particles increased the release of MMP-1. Northern blotting showed elevated mRNA signal levels for MMP-1, MMP-2, and MMP-9 after exposure to both types of particle. Collagenolytic activity also increased in the macrophage culture medium in response to both types of particle.

Our findings support the hypothesis that macrophages release MMPs in proportion to the amount of particulate debris within periprosthetic tissues.


The Journal of Bone & Joint Surgery British Volume
Vol. 80-B, Issue 3 | Pages 531 - 539
1 May 1998
Goodman SB Huie P Song Y Schurman D Maloney W Woolson S Sibley R

The tissues surrounding 65 cemented and 36 cementless total joint replacements undergoing revision were characterised for cell types by immunohistochemistry and for cytokine expression by in situ hybridisation.

We identified three distinct groups of revised implants: loose implants with ballooning radiological osteolysis, loose implants without osteolysis, and well-fixed implants. In the cemented series, osteolysis was associated with increased numbers of macrophages (p = 0.0006), T-lymphocyte subgroups (p = 0.03) and IL-1 (p = 0.02) and IL-6 (p = 0.0001) expression, and in the cementless series with increased numbers of T-lymphocyte subgroups (p = 0.005) and increased TNFα expression (p = 0.04). For cemented implants, the histological, histochemical and cytokine profiles of the interface correlated with the clinical and radiological grade of loosening and osteolysis.

Our findings suggest that there are different biological mechanisms of loosening and osteolysis for cemented and cementless implants. T-lymphocyte modulation of macrophage function may be an important interaction at prosthetic interfaces.