P. Cherubino

Autologous chondrocyte implantation using a bilayer collagen membrane: A preliminary report

Purpose. To present preliminary clinical experience with Matrix-induced autologous chondrocyte implantation, a new tissue-engineering technique for treatment of deep cartilage defects, in which autologous chondrocytes are seeded on a tridimensional scaffold provided by a bilayer type I–III collagen membrane. Methods. From December 1999 to January 2001, 13 patients underwent implantation procedure for deep cartilage defects. Age of patients ranged from 18 to 49 years (mean age, 35 years). The mean defect size was 3.5 cm2 (range, 2.0–4.5 cm2). Clinical and functional evaluation were performed using various score systems for the ankle and the knee, and magnetic resonance imaging was performed at 6 and 12 months postoperatively. Membrane structure and cellular population were investigated by light microscopy, scanning electron microscopy, and electrophoresis before implantation. Results. The mean follow-up was 6.5 months (range, 2–15 months). No complications were observed in the postoperative period. The 6 patients with a minimum follow-up of 6 months showed an improvement in clinical and functional status after surgery. Magnetic resonance images showed the presence of hyaline-like cartilage at the site of implantation; there was evidence of chondroblasts and type II collagen inside the seeded membrane. Conclusion. Matrix-induced autologous chondrocyte implantation offers several advantages with respect to the traditional cultured cell procedure. These include technical simplicity, short operating time, minimal invasiveness, and easier access to difficult sites. It appears to be a reliable method for the repair of deep cartilage defects.

Application of BMP-7 to tibial non-unions: A 3-year multicenter experience

SUMMARY The effective treatment of the often debilitating, longlasting and large-asset-consuming complication of fracture non-unions has been in the centre of scientific interest the last decades. The use of alternative bone substitutes to the gold standard of autologous graft includes the osteoinductive molecules named bone morphogenetic proteins (BMPs). A multicenter registry and database (bmpusergroup.co.uk) focused on the application of BMP-7/OP-1 was created in December 2005. We present the preliminary results, using the prospective case-series of aseptic tibial non-unions as an example. Sixty-eight patients fulfilled the inclusion criteria for this observational study, with a minimum follow-up of 12 months. The median duration of tibial non-union prior to BMP-7 application was 23 months (range 9-317 mo). Patients had undergone a median of 2 (range 0-11) revision procedures prior to the administration of BMP-7. In 41% the application of BMP-7 was combined with revision of the fixation at the non-union site. Non-union healing was verified in 61 (89.7%) in a median period of 6.5 months (range 3-15 mo). No adverse events or complications were associated with BMP-7 application. The safety and efficacy of BMP-7 was verified in our case series, and was comparable to the existing evidence. The establishment of multicenter networks and the systematic and long-term follow- up of these patients are expected to provide further information and significantly improve our understanding of this promising osteoinductive bone substitute.

Adverse effects associated with non-opioid and opioid treatment in patients with chronic pain.

Chronic pain is a debilitating condition that is associated with many common diseases; this places a major burden on the healthcare system. There are currently numerous analgesic agents available for the treatment of chronic pain. In general, the oral non-opioid analgesic, paracetamol, is recommended for the initial treatment of mild to moderate pain. Therapeutic doses of paracetamol do not appear to result in hepatotoxicity, although overdose may lead to acute liver failure. Current data suggest that paracetamol has acceptable gastrointestinal tolerability. Another class of non-opioid analgesic with confirmed efficacy for the treatment of chronic mild to moderate pain are non-steroidal anti-inflammatory drugs (NSAIDs), although this efficacy is offset by the potential of adverse gastrointestinal events. In particular, non-selective NSAIDs, also known as cyclooxygenase (COX) inhibitors, carry an increased risk of serious upper gastrointestinal complications, including ulcers, perforation and bleeding. The introduction of COX-2 inhibitors provided a NSAID-based option with improved gastrointestinal safety, but increased risk of cardiovascular effects. Opioids are powerful analgesic agents used to treat moderate to severe chronic pain. However, treatment with opioids is associated with a number of common adverse effects, including constipation, nausea or vomiting, pruritus, somnolence or cognitive impairment, dry mouth, tolerance or dependence and urinary retention. Although there are multiple strategies in place to manage adverse events that arise from both non-opioid and opioid analgesic therapy, a better understanding of the mechanisms involved in the development of specific drug-related adverse effects is required along with proper prescribing practices and adequate physician/patient education. Balanced against the adverse effects of pain management medications, there is a need to be mindful of the widespread, often serious, adverse consequences of poorly managed pain itself.Chronic pain is a debilitating condition that is associated with many common diseases; this places a major burden on the healthcare system. There are currently numerous analgesic agents available for the treatment of chronic pain. In general, the oral non-opioid analgesic, paracetamol, is recommended for the initial treatment of mild to moderate pain. Therapeutic doses of paracetamol do not appear to result in hepatotoxicity, although overdose may lead to acute liver failure. Current data suggest that paracetamol has acceptable gastrointestinal tolerability. Another class of non-opioid analgesic with confirmed efficacy for the treatment of chronic mild to moderate pain are non-steroidal anti-inflammatory drugs (NSAIDs), although this efficacy is offset by the potential of adverse gastrointestinal events. In particular, non-selective NSAIDs, also known as cyclooxygenase (COX) inhibitors, carry an increased risk of serious upper gastrointestinal complications, including ulcers, perforation and bleeding. The introduction of COX-2 inhibitors provided a NSAID-based option with improved gastrointestinal safety, but increased risk of cardiovascular effects. Opioids are powerful analgesic agents used to treat moderate to severe chronic pain. However, treatment with opioids is associated with a number of common adverse effects, including constipation, nausea or vomiting, pruritus, somnolence or cognitive impairment, dry mouth, tolerance or dependence and urinary retention. Although there are multiple strategies in place to manage adverse events that arise from both non-opioid and opioid analgesic therapy, a better understanding of the mechanisms involved in the development of specific drug-related adverse effects is required along with proper prescribing practices and adequate physician/patient education. Balanced against the adverse effects of pain management medications, there is a need to be mindful of the widespread, often serious, adverse consequences of poorly managed pain itself.

Application of bone morphogenetic proteins to femoral non-unions: a 4-year multicentre experience

Fracture non-unions often complicate orthopaedic trauma. BMPs (bone morphogenetic proteins) are currently considered the most appealing osteoinductive agents. Applications of BMP-7 since January 2004 were prospectively recorded in a multicentre registry of aseptic femoral non-unions. The study included 30 patients who had undergone a median of 1 revision operation before BMP-7 application and who were followed up for a median 24 months. In 23/30 cases the application of BMP-7 was combined with revision of the fixation, and in 12 it was combined also with autograft. Non-union healing was verified in 26/30 cases in a median period of 6 months. No adverse events were associated with BMP-7 application. Our case series supports the safety and efficacy of BMP-7 in femoral non-unions. Multicentre networks and systematic, long-term follow-up of patients may improve understanding of this promising osteoinductive bone substitute.

Clinical applications of growth factors in bone injuries: Experience with BMPs

The management of open fractures and delayed or non unions continue to be complicated by high rates of treatment failure and significant patient disability and dissatisfaction. The use of bone morphogenetic proteins (BMPs) in the treatment of these injuries has been assessed by several authors. BMPs induce the process of bone healing by recruiting bone-forming cells to the area of lesion. The use of BMP currently has two FDA-approved indications: treatment of open tibial fractures treated with intramedullary fixation and treatment of tibia long bone non-union. Despite this limited target, off-label BMP use continues to push the spectrum for new applications. This review describes the current evidence for the use of BMPs in open fractures and non-unions.

The Appropriate Treatment of Chronic Pain

Chronic pain is a common healthcare problem worldwide that ranks as a predominant reason for consulting a physician, yet effective management of chronic pain remains suboptimal, often resulting in unnecessary suffering and decreased quality of life, lost productivity and excessive healthcare costs. To overcome the challenges associated with the management of chronic pain, increased awareness and both patient and physician education are required. Improving physician knowledge of pain assessment and management guided by recommendations for a comprehensive, multifactorial, personalised treatment approach involving pharmacological and non-pharmacological approaches is key to achieving effective pain relief. Guidelines for the management of non-cancer and cancer pain recommend thorough patient assessment before individualized therapy based on the type and intensity of pain. The availability of mechanism-specific analgesics has facilitated improvements in the treatment of chronic non-cancer pain, which may be of neuropathic, muscle, inflammatory, mechanical/compressive or mixed origin. Stepwise escalation of analgesic therapy (paracetamol, non-steroidal anti-inflammatory drugs, mild to strong opioids) according to the World Health Organization’s three-step pain ladder remains the standard approach for the selection of treatment for chronic cancer pain, although there is now a greater awareness of the requirements for effective administration of opioids including dose titration, use of short versus long-acting opioids, opioid rotation, management of adverse effects, and ongoing monitoring. Selection of an effective, appropriate, personalized analgesic regimen for patients with chronic pain is achievable and is expected to enhance compliance, overall functioning and quality of life.

Barriers to pain management : focus on opioid therapy.

Despite the availability of effective pain treatments, there are numerous barriers to effective management resulting in a large proportion of patients not achieving optimal pain control. Chronic pain is inadequately treated because of a combination of cultural, societal, educational, political and religious constraints. The consequences of inadequately treated pain are physiological and psychological effects on the patient, as well as socioeconomic implications. Unreasonable failure to treat pain is viewed as unethical and an infringement of basic human rights. The numerous barriers to the clinical management of pain vary depending on whether they are viewed from the standpoint of the patient, the physician, or the institution. Identification and acknowledgement of the barriers involved are the first steps to overcoming them. Successful initiatives to overcome patient, physician and institutional barriers need to be multifaceted in their approach. Multidisciplinary initiatives to improve pain management include dissemination of community-based information, education and awareness programmes to attempt to change attitudes towards pain treatment. A better awareness and insight into the problems caused by unrelieved pain and greater knowledge about the efficacy and tolerability of available pain management options should enable physicians to seek out and adhere to treatment guidelines, and participate in interventional and educational programmes designed to improve pain management, and for institutions to implement the initiatives required. Although much work is underway to identify and resolve the issues in pain management, many patients still receive inadequate treatment. Continued effort is required to overcome the known barriers to effective pain management.Despite the availability of effective pain treatments, there are numerous barriers to effective management resulting in a large proportion of patients not achieving optimal pain control. Chronic pain is inadequately treated because of a combination of cultural, societal, educational, political and religious constraints. The consequences of inadequately treated pain are physiological and psychological effects on the patient, as well as socioeconomic implications. Unreasonable failure to treat pain is viewed as unethical and an infringement of basic human rights. The numerous barriers to the clinical management of pain vary depending on whether they are viewed from the standpoint of the patient, the physician, or the institution. Identification and acknowledgement of the barriers involved are the first steps to overcoming them. Successful initiatives to overcome patient, physician and institutional barriers need to be multifaceted in their approach. Multidisciplinary initiatives to improve pain management include dissemination of community-based information, education and awareness programmes to attempt to change attitudes towards pain treatment. A better awareness and insight into the problems caused by unrelieved pain and greater knowledge about the efficacy and tolerability of available pain management options should enable physicians to seek out and adhere to treatment guidelines, and participate in interventional and educational programmes designed to improve pain management, and for institutions to implement the initiatives required. Although much work is underway to identify and resolve the issues in pain management, many patients still receive inadequate treatment. Continued effort is required to overcome the known barriers to effective pain management.

The unstable total hip replacement

Background: Dislocation is one of the most common complications of total hip arthroplasty with a reported dislocation rate of 3.2%. Despite increased experience with hip replacement, the overall rate has not yet changed. The aim of this paper is to review the most recent literature published on this topic and indexed in Medline, in order to clarify the main risk factors, and to standardize a treatment protocol of such an important complication of prosthetic surgery. Materials and Methods: Medline database was searched using key words: “hip dislocation”, “hip instability” from 1980-2007. Studies were eligible for review and included if they met the following criteria: (1) publication in English, (2) clinical trials (3) review papers. Results: The risk of first-time dislocation as a function of time after the surgery is not well understood. Most, but not all, series have demonstrated that the risk of dislocation is highest during the first few months after hip arthroplasty; however, first-time late dislocation can also occur many years after the procedure. Several risk factors were described, including the surgical approach, the diameter of the head, impingement, component malposition, insufficient abductor musculature. In addition, there are also many treatment options, such as long-term bracing after closed reduction, component reorientation, capsulorraphy, trochanteric advancement, increasing offset, exchange of the modular head and the polyethylene liner, insertion of constrained liner. Conclusion: Preventing hip dislocation is obviously the best strategy. Surgeons must take into account patient and surgical risk factors. For patients at high risk for dislocation the surgeon should accurately restore leg length and femoral offset; the use of larger femoral heads, posterior transosseous repair of the capsulotendinous envelope if posterior approach is chosen or the use of a lateral approach should be considered. Proper patient education and postoperative care are very important.

The management of chronic pain in important patient subgroups.

Chronic pain is a major healthcare issue in Europe and globally, and inadequate or undertreated pain significantly reduces the ability of many patients to participate in ordinary daily activities, adversely affects their employment status and contributes to a substantial rate of depression and anxiety in patients with chronic pain. There is a broad distinction of chronic pain into chronic non-cancer pain and chronic cancer pain, and important subgroups of these include patients with rheumatic and/or orthopaedic diseases, pain syndromes caused by cancer itself and caused by cancer treatment. Despite comprising the majority of non-cancer pain in Europe, chronic non-cancer pain associated with rheumatic diseases and/or orthopaedic conditions is often inadequately managed. Although paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) play a continuing role in the treatment of chronic rheumatic diseases, accumulating evidence of potential toxicity with both traditional non-selective NSAIDs and selective cyclooxygenase 2 inhibitors has prompted a reassessment of their use. This has particular resonance for the elderly, who are more likely to have significant pain issues than younger patients and are at high risk of NSAID-related adverse events. The use of mild opioids, such as codeine and tramadol, and strong opioids, such as morphine, hydromorphone and oxycodone, may be appropriate where paracetamol and other non-opioid analgesics are ineffective in chronic non-cancer pain. Cancer pain, either related to the underlying disease or caused by cancer treatment, is also a common cause of chronic pain in the elderly. An understanding of individual needs is essential in providing adequate pain relief, which is a central goal of care in all patients with chronic pain.Chronic pain is a major healthcare issue in Europe and globally, and inadequate or undertreated pain significantly reduces the ability of many patients to participate in ordinary daily activities, adversely affects their employment status and contributes to a substantial rate of depression and anxiety in patients with chronic pain. There is a broad distinction of chronic pain into chronic non-cancer pain and chronic cancer pain, and important subgroups of these include patients with rheumatic and/or orthopaedic diseases, pain syndromes caused by cancer itself and caused by cancer treatment. Despite comprising the majority of non-cancer pain in Europe, chronic non-cancer pain associated with rheumatic diseases and/or orthopaedic conditions is often inadequately managed. Although paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) play a continuing role in the treatment of chronic rheumatic diseases, accumulating evidence of potential toxicity with both traditional non-selective NSAIDs and selective cyclooxygenase 2 inhibitors has prompted a reassessment of their use. This has particular resonance for the elderly, who are more likely to have significant pain issues than younger patients and are at high risk of NSAID-related adverse events. The use of mild opioids, such as codeine and tramadol, and strong opioids, such as morphine, hydromorphone and oxycodone, may be appropriate where paracetamol and other non-opioid analgesics are ineffective in chronic non-cancer pain. Cancer pain, either related to the underlying disease or caused by cancer treatment, is also a common cause of chronic pain in the elderly. An understanding of individual needs is essential in providing adequate pain relief, which is a central goal of care in all patients with chronic pain

Culture of skeletal myoblasts from human donors aged over 40 years: dynamics of cell growth and expression of differentiation markers.

BackgroundLocal myogenesis, neoangiogenesis and homing of progenitor cells from the bone marrow appear to contribute to repair of the infarcted myocardium. Implantation into heart tissues of autologous skeletal myoblasts has been associated with improved contractile function in animal models and in humans with acute myocardial ischemia. Since heart infarction is most prevalent in individuals of over 40 years of age, we tested whether culture methods available in our laboratory were adequate to obtain sufficient numbers of differentiated skeletal myoblasts from muscle biopsy specimens obtained from patients aged 41 to 91.Methods and resultsNo matter of donor age, differentiated skeletal muscle cells could be produced in vitro in amounts adequate for cellular therapy (≥300 millions). Using desmin as a cytoplasmic marker, about 50% cultured cells were differentiated along myogenic lineages and expressed proteins proper of skeletal muscle (myosin type I and II, actin, actinin, spectrin and dystrophin). Cytogenetic alterations were not detected in cultured muscle cells that had undergone at least 10 population doublings. Molecular methods employed for the screening of persistent viral infections evidenced that HCV failed to replicate in muscle cells cultured from one patient with chronic HCV infection.ConclusionThe proposed culture methods appear to hold promise for aged patients not only in the field of cardiovascular medicine, but also in the urologic and orthopedic fields.