Summary Statement

An Implant Disposable Antibacterial Coating (i-DAC®) is described, consisting of a fully resorbable, biocompatible hydrogel, able to release antibacterial and antibiofilm agents. Direct application of the hydrogel on implants prevented infection occurrence in an in vitro model of peri-prosthetic infection.

Introduction: Various antibiotic coatings have been proposed to prevent bacteria colonization and infection of orthopaedic implants. While most of the available technologies seem to provide an effective implant protection from infection, unknown long-term effects of antibiotic coatings raise some concerns for extensive application. Aim of the present study was to develop and test a new fast-resorbable antibacterial carrier to be used as a temporary coating to prevent early bacteria colonization of metallic implants.

Methods: The patented tested hydrogel is a co-polimer comprising hyaluronic acid (HA) and a biocompatible polyester (poly-lactic acid) with or without polyethylene glycol chains to further modulate hydrophilicity and anti-fouling characteristics of the compound. The HA derivative is then added to water and mixed, just before its use, with the chosen antibacterial agent. For the purpose of this study, different HA-PLA derivatives have been tested, with two vancomycin and tobramycin concentrations and manually spread to uniformly cover the surface of a titanium specimen. To evaluate the release of vancomycin or tobramycin, high performance chromatographic analysis (HPLC) was carried out.

Results: Antibacterial hydrogels provided vancomycin release ranging from 47 % to 80 % in two hours to 100 % (complete release) in 24 to 72 hours, with antibiotic concentrations up to 400 times the minimum inhibiting concentration. The combined release of the two antibiotics (1 % w/v) showed 26.8 % release of vancomycin and 35.8 % of tobramycin at 2 hours and complete release at 72 hours. Doubling antibiotic concentration (2 % w/v), yielded 56.6 % and 76.6 % antibiotic release, respectively for vancomycin and tobramycin at 2 hours and complete release at 48 hours.

Discussion and Conclusion: HA chemical derivatization with polyesters leads to the formation of copolymers which can be used to produce antibacterial hydrogels with promising applications in the orthopedic field. These antibacterial hydrogels are in fact easily prepared and spread over a surface, showing the ability of releasing high concentrations of antibiotics for a desired, limited, period of time. Adding antibiotics to the hydrogel just before its use, allows customized antibiotic choice and dosing, avoiding shelf-life problems.

This technical choice constitutes an effective solution for all those cases where, due to the infective damage, the radical surgical debridement needed or in presence of a septic pseudoarthrosis, there is a relevant loss of bone stock in the proximal femur.

As a treatment for these specific clinical patterns oncological prosthetic implants can be used, to overcome the amount of bone loss.

Sometimes acetabular prosthetic implantation, or reimplantation, is also needed because of its septic mobilization, otherwise a bicentric endoprosthesis can be implanted.

The main issue for the surgeon is the gluteal muscular deficiency, caused often by the loss of the great trochanter, a severe condition often worsened by the damage on muscles and soft tissues given by previous surgical procedures and debridements.

The offset itself, really often not sufficient for the limited amount of sizes and lengths of the oncological designed prosthetic implants, represent a key issue of this treatment with a high luxation risk, with a higher rate in those cases when an arthroprosthesis has been performed.

In this article are described 4 cases, all four treated with a two-stage surgical approach and a definitive oncological prosthetic system to overcome the severe bone loss of the proximal femur.

The cases are examined about the surgical indication to this prosthetic choice, the postoperative period with the related complications (1 case of recurrent luxation) and with a minimum follow up of 6 months (maximum 36 months).

In all the cases at the follow up the infection is solved.

At the end the specific rehabilitation program for the range of motion and the muscular strength regain, that we developed in our Operative Unit is described; in this program we occasionally used for the immediate post surgery period a jointed hip brace.

The length of the rehabilitation could not be standard, but should be customized and variations of the program could be done during the follow up.

In the immediate post-surgical period the rehabilitative goals are maintaining the correct posture in bed and regaining the passive articular range of motion.

In the longer period the main goals are regain strength of the gluteal muscles, proprioception and gait, even if claudication (Trendelemburg), hyposthenia a recurrent dislocation can be let.

The weight bearing is allowed usually at the eight week after surgery, but only after clinical and x-ray evaluation.

Two-stage revision is the most widely accepted and performed intervention for chronically infected joint prosthesis. The choice of this option relies on the following considerations:

higher antibiotic concentrations may be used in the spacers, compared to the cement used for prosthetic fixation in a single-stage procedure, since high dose antibiotic-loaded cement may be too fragile for long term prosthesis fixation (Bucholz, 1986);

Two-stage reimplantation using an articulated interval spacer of antibiotic-impregnated bone-cement has been previously investigated and proved as an effective Method:

to adequately fill the void created by the implant removal,

However a considerable variation in the form and function of interval spacers exists. A spacer may in fact be commercially made, or it may be custom-made in the operating room. It may be made entirely of polymethylmethacrylate cement, or it may be a cement-coated metal composite. Favorable results have been reported with each of these types of spacers.

Preformed antibiotic-loaded spacers (InterSpace® Hip and InterSpace® Knee, Tecres SpA, Verona, Italy – Hexactech Inc. Gainesville, Florida) offer:

known mechanical resistance;

Introduction: Staphylococci are a well recognized cause of orthopaedic implant infections, due to their ability to produce biofilms, that limit antibiotic and host defence capabilities. To detect serum IgM levels against staphylococcal slime polysaccharide antigens (SSPA), an original immunoenzymatic assay has been previously developed and tested in patients affected by staphylococcal vascular graft infections [The Lancet • 359:2166–2168, 2002]. This is the first report on the efficacy of this serum ELISA testing of anti-SSPA IgM in Staphylococcal Orthopaedic Implant-Related Infections (SOIRI).

Methods: SSPA is extracted and purified using a suitable original patented bacterial strain and method. The immunoenzymatic assay to detect anti-SSPA IgM was performed on sera collected from 53 patients with joint prosthesis (24 hips, 17 knees, 2 shoulders). Each serum sample was tested in triplicate in two different assays and values are expressed as means. Main exclusion criteria were: time from implant < 6 months, rheumatoid arthritis, concurrent known infections. The study was approved by the local ethical committee and all patients gave their informed consent.

28 sera were collected from controls (patients with uninfected joint prosthesis, as judged from clinical, laboratory and radiological data) and 25 sera were obtained from patients with known SOIRI, sustained by S. aureus or coagulase-negative Staphilococci (CNS) (positive joint aspiration and/or intra-operative cultural examination).

Results: 25 patients were classified as true negative, 21 true positive, 4 false negative, 3 false positive. Test efficacy calculation provided the following Results: sensitivity: 84 %, specificity: 89.3 %, positive predictive value: 87.5 %, negative predictive value: 86.2 %.

Discussion and Conclusion: Anti-SSPA IgM immunoenzymatic assay showed interesting sensitivity and specificity in this preliminary prospective study. The test appear as an innovative, user-friendly, cheap and non-invasive diagnostic tool for orthopaedic implant-related infections. Further studies should be devoted to better define the cut-off value, testing reproducibility and standardization for large scale application.

Reasons for bone loss in septic hip prosthesis include osteolysis caused by the infection in itself and by the mechanical loosening, while implant removal and the necessary bone debridment usually ends in a even more severe bone loss.

In two stage revision surgery the use of a long stem antibiotic-loaded pre-formed cement spacer (Spacer G – Tecres s.r.l., Italy) appears particularly useful to allow mechanical stability and antibiotic local elution even in the presence of wide proximal femoral bone loss. After two months the revision is performed with non-cemented long stem modular implants (Profemur – Wright-Cremascoli) without the need for massive bone grafts. Recently we have also started using growth factors to stimulate bone stock reconstitution. In all the patients a double antibiotic therapy is administered after the first and second stage procedures for 6–8 weeks.

The results obtained (54 patients, follow-up 2 – 5 years) according to this protocol show the absence of infection recurrence, 10 cranial spacer dislocation, not treated, 2 revision prosthesis dislocations, that required open reduction, 1 transient femoral nerve palsy.

The described technique, used according to a proper protocol, allows to obtain good results, in the medium term follow-up.

Septic knee prosthesis revision is particularly challenging either for the eradication of the infection and for functional recovery of the patient.

18 patients treated from year 2000 to 2003, treated according to the same medical and surgical protocol have been reviewed. In all cases the following steps have been followed:

- removal of the septic prosthesis, debridement and implant of an articulated pre-formed cement spacer;

At a mean 18 months follow-up, we observed:

- no infection recurrence in all cases (one patient is lost to follow-up);

Two-stage septic knee prosthesis revision, according to a the described protocol, allows to obtain high infection eradication rate and acceptable functional recovery, in the medium term follow-up.

Different conditions may lead to bone loss in bone infections. Septic non-unions, osteomyelitis, septic joint prosthesis are all conditions that may be associated with the need for bone grafts and/or of bone substitutes. The risk of infection recurrence makes, in these cases, particularly challenging the choice of the type of bone implant.

The use of growth factors, eventually associated with autologous or homologous bone grafts or with bone substitutes, may be helpful in restoring the bone stock, allowing to fill large bone defects, once the infection is controlled.

We present the preliminary results in 10 patients in which autologous Platelet Rich Plasma (PRP) has been used to treat large bone defect in two stage hip reconstruction (7 cases) and in previously infected non-unions (3 patients).

At a minimum follow-up of 6 months (maximum 18 months) a significant new bone formation occurred at the site of PRP application in all the cases treated and no signs of infection recurrence are present at the time of writing.

This is the first report on the short-term safety of use of PRP for the treatment of bone loss in previously infected bones in humans. The limited number of patients and the follow-up do not allow at the moment to drive any conclusion regarding the efficacy and safety in the long term, and the use of PRP with this indications should be limited to selected cases.

Introduction: The problems of the differential diagnosis (d.d.) between musculoskeletal infections and tumours are generally uncommon because both pathologies are quite rare. This is not the experience at the G. Pini Orthopaedic Institute where there are two Units specialized on bone infections and bone tumours and their clinicians often consult each other for difficult cases.

Material and Methods: On the basis of this experience, the A.A. revised clinical and radiological criteria of d.d. between acute or chronic osteomyelitis and different histotypes of musculoskeletal tumours. In particular they examined the type and the course of the symptoms, the laboratory data, the site of the lesions and the characteristics of the imaging, both for bone damages and for soft tissues invasion. Afterwards they compared this revision whit the experience of the cases consulted each other.

Results: D.d. of acute osteomyelitis include Ewing sarcoma, Osteosarcoma and Eosinofilìe granuloma, especially in children; d.d. of chronic and deep lesions (axial skeleton) in adults include lymphoma and metastasis; in the epiphysis d.d. can involve also benign lesions. This work allowed the A.A. to identify some guidelines that they consider suitable. Time, possibilities and limits of the imaging techniques like bone scans, CT and MRI are outlined, likewise time and types of direct examination of the lesions by puncture or biopsy, that was necessary in many cases, are proposed.

Conclusions: The A.A. think that these personal guidelines can help them to face easier, in the future, the difficult cases, minimizing both diagnostics and therapeutics delays and mistakes.

Introduction: Reports about the usefulness of FDG-PET in detecting infections were few in the last years but are greatly increasing in number in the recent years. The interest for this method is related to the demonstration that FDG uptake is increased in cells with elevated glycolitic activity as neoplastic cells, neutrophils, activated macrophages, probably bacteria. As far as a neoplasm is excluded, FDG uptake is increased in inflammatory sites. This study was done to test the possible use of this method in painful total hip-replacement diagnosis.

Materials and methods: A prospective study on 24 patients (33 hip arthroplasties) affected by painful total hip replacement was conducted. All patient has blood test, X-ray examinations of hips and chest, Ultrasound scan, cultures from sinus tract or hip aspiration, Tc^99m MDC bone scan (SPECT), FDG-PET. Areas of uptake were evaluated and compared. Fifteen patients were operated on (9 two-stage revisions, debridements), during operation cultures were repeated and bone biopsy were done at the sites of icreased PET uptake. Bone and soft tissue debridement was specifically performed on site of PET uptake with maximal preservation of bone stock.

Results: Infected hips were 20. Infection was demonstrated by positive culture and positive biopsy in all cases. Sensibility and specificity of PET were respectively 100% and 92%. The study of tracers uptake showed that these are complementary and give different information. All patients who were operated on were reviewed with a mean follow up of 7 months (range 3 months-15 months ). The nine patients who had revision were free of infection at follow-up.

Discussion: from our experience PET is easy to perform, has an excellent sensibility and good specificity and can be placed at the end point of the flow-chart for diagnosis of total hip replacement infection (preceeded in any case by standard X-Rays and bone scan). Moreover PET scan could be useful in pre-operative planning of revision surgery as it has better anatomical definition than traditional scans and may allows surgeon to localize on three planes infected bone and soft tissues. Therefore at the moment this tool has high costs so should be used in selected cases. Its real usefulness in revision surgery has to be confirmed by a longer follow-up of treated cases.

Introduction: In 1995 we started using, at the G. Pini Orthopaedic Istitute of Milano, a system for bone healing stimulation based on low intensity pulsed ultrasound. Advantages of the method are: home therapy (20 minutes per day); no side effects, even in the presence of metallic devices or infection; ease of use. Indications of low intensità pulsed ultrasound are bone healing after fresh frarctures, in which a significant bone healing accelation can be observed, delayed and non-unions. We share our experience in a challenging field of application: septic non-unions.

Materials and methods: We retrospectively evaluated 30 patients, treated from 1996 to 2003, affected by septic non-unions (a fracture that, in the presence of infection, did not show any significant increase in callus formation at 8 months from the time of fracture). The patients had a mean 1.7 ± 2 previous failed intervention. Patients were treated, in the absence of other medical or surgical treatment (excluding antibiotic therapy), with low intensity pulsed ultrasound (EXOGEN S.A.F.H.S. or, since year 2002, IGEA F.A.S.T.). The treatment was applied, after the necessary instructions, directly from the patient, at home, 20 minutes per day. Failures of the treatment were considered need for further surgery to stimulate bone healing, persistence of non-union at follow-up. Exclusion criteria included: evident instability of the synthesis, soft tissue loss and bone exposure, wide bone loss (> 2 cm).

Results: 24 bone healing (86 %), 4 failures (need for surgery), 2 treatment discontinuation. Mean treatment duration: 123 ± 43 days (minimum 90, maximum 240 days). No side effects local or general were observed. In 18 cases a bone debridment and/or hardware removal intervention had been performed after bone healing. At follow-up, 28 patients are free from infection, while two showed infection recurrence.

Conclusions: Low intensity pulsed ultrasound is an effective options in the treatment of septic non-unions, without side effects. An accurate indication and patient selection provide an advantageous cost/benefit ratio.

A prospective study on 24 patients (33 hip arthroplasties) affected by painful total hip replacement was conducted. All patient had a blood test, X-rays, ultrasound scan, cultures, Tc ^99m bone scan (SPECT), and F¹⁸FDG-PET. Fifteen patients were operated on (nine two-stage revisions, six débridements). During operation, cultures were repeated and bone biopsy was performed at the sites of increased PET uptake. Bone and soft tissue débridement was specifically performed at the site of PET uptake with maximal preservation of bone stock.

There were 20 infected prostheses. Infection was demonstrated by positive culture in all cases and positive biopsy in operated cases. Sensibility and specificity of PET were 100% and 92%, respectively. All patients who were operated on were reviewed with a mean follow-up of 7 months. The nine patients who had revision were free of infection at follow-up.

In our experience PET is easy to perform, has an excellent sensitivity and good specificity and can be placed at the end point of the flow-chart for diagnosis of total hip replacement infection. Moreover, PET scan could be useful in pre-operative planning of revision surgery as it has better anatomical definition than traditional scans. Presently, it involves high costs and should only be used in selected cases. Its real usefulness in revision surgery has to be confirmed by a longer follow-up of treated cases.

Bone loss, either due to a septic process or to surgical débridements, is frequently associated with bone infections. Bone loss may be present in septic non-unions, osteomyelitis or septic joint prosthesis. In each of these conditions the use of bone or bone substitutes may be indicated. However, the risk of septic recurrence makes the choice of the right implant in these patients particularly difficult.

Clinical cases are presented to show the different choices available. Attention is focussed on: (1) when, in the presence of bone loss, a bone graft can be avoided and with which suitable procedures good results can be obtained; (2) when and how autologous bone grafts should be used; (3) when homologous bone grafts or bone substitutes are indicated; (4) how bone grafts should be protected against bacterial adesion and proliferation; and (5) the role of new technologies, such as bone growth factors. In this regard the clinical results are presented of the use of platelet-rich plasma (PRP) added to autologous or homologous bone after bone débridement in six patients treated with two-stage non-cemented revision of septic hip prosthesis and in two patients with septic non-union of the femur. At a minimum follow-up of 6 months (max. 1 year), we did not observe any infection recurrence, while bone remodelling and clinical outcome were favourable.

The use of bone growth factors such as PRP possibly added to autologous or homologous bone appears to be a promising technique to achieve bone reconstruction in débrided bone infections. However, with the limited numbers of patients and the short-term follow-up conclusions cannot be drawn and the use of growth factors with this indication should be limited to selected cases: patients with wide bone loss and with no signs of active infections.

No international guidelines are available concerning bone reconstruction in infections. Clinical experience shows that different surgical procedures are effective and the choice should take into considerations the type and site of bone defect, the host type and the pathogenesis of the bone loss. Growth factors may be a useful tool in these conditions and further studies are indicated.

A modular neck allows to choose the offset of the femoral head and the degree of anti-retroversion, lateralization and varus-valgus intraoperatively. At the G. Pini Institute we have been using modular necks in custom prostheses since 1989. Excellent results in this application did open the way to a larger use in off-the-shelf prostheses. Modular necks can be now coupled with different stems, leaving the surgeon free to use the preferred prosthetic stem design. Modular necks have been implanted in more than 50,000 in the world. Medium term results in custom prosthesis and the experience in off-the-shelf non-cemented stems are presented, together with further improvements of this technology under study.

From 1989 to December 1999, 481 custom stems have been implanted. All patients but ten received modular necks. The prostheses were made of a titanium alloy and HA coated. 61 % of patients had dysplastic oxarthrosis. 372 implants performed between 1989 and 1996 were retrospectively evaluated. Data from off-the-shelf prosthesis, at a shorter follow-up, are also reported. Laboratory data showed that the use of an elliptical Morse cone of the neck reduced wear debris production to less than 1 mg/year. In custom implants, (mean follow-up: 7 years), we did not observe any thigh pain or radiological signs of osteolysis or fretting. Mean leg-length discrepancy was 2.8 cm pre-op and 0.3 cm post-operatively. Off-the-shelf implants also showed good clinical and radiological results. New design modular necks will increase the possible range of motion and provide more solutions for positioning the center of rotation. Modular neck is a safe and reliable solution to obtain the correct position of the center of rotation intra-operatively, without side effects. Applications in off-the-shelf prostheses allow to reduce costs while maintaining the advantages of this technology.