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Knee Complaints Vary With Age And Gender In The Adult
Population-based reference data for the Knee Injury and Osteoarthritis Outcome Score (KOOS)
Authors: Przemyslaw T Paradowski, Stefan Bergman, Anne Sundén-Lundius,
L Stefan Lohmander and Ewa M Roos

Department of Orthopedics, Clinical Sciences, Lund University Hospital, Sweden; The Department of Reconstructive Surgery and Arthroscopy of the Knee, Medical University Hospital, Poland; Spenshult Hospital for the Rheumatic Diseases, Sweden; Department of Physical Therapy, Health Sciences, Lund University Hospital, Sweden

Regenerative Approaches to the Repair of Cartilage Defects
Author: Dr. Carola Dony, Scil Technology GmbH

The Physician Entrepreneur in the U.S.
Author: Dr. James K. Brannon, Founder, President
and C.E.O. of Orthopedic Sciences, Inc.

BOA 2006




Knee Complaints Vary With Age And Gender In The Adult
Population-based reference data for the Knee Injury and Osteoarthritis Outcome Score (KOOS)

Authors: Przemyslaw T Paradowski, Stefan Bergman, Anne Sundén-Lundius,
L Stefan Lohmander and Ewa M Roos

Department of Orthopedics, Clinical Sciences, Lund University Hospital, Sweden; The Department of Reconstructive Surgery and Arthroscopy of the Knee, Medical University Hospital, Poland; Spenshult Hospital for the Rheumatic Diseases, Sweden; Department of Physical Therapy, Health Sciences, Lund University Hospital, Sweden

Background
 Disability of the knee is a common problem across the population. In most population-based epidemiological studies singe-item questions are used to estimate the prevalence of knee pain. To assess the outcome of interventions due to knee injury and knee osteoarthritis however, the use of multi-item knee-specific outcome measures giving a broader picture of the clinical status is recommended1,2. One such instrument is the Knee injury and Osteoarthritis Outcome Score (KOOS) which has been validated for anterior cruciate ligament reconstruction3, meniscectomy4 and total knee replacement5, procedures performed in different age groups of the adult population.

Several studies using other knee-specific outcome scores have shown that the average score for a control group rarely is equivalent to the best possible score and also indicated differences due to age and gender6-8.

Thus, it is essential to establish reference data from the general population to determine the influence of demographic factors such as age and gender on the perceived self-reported knee status of patients, and consequently better determine the true impact of treatment strategies. There is a paucity of studies that investigate knee pain, knee function and knee-related quality of life across the adult population. Population based studies have this far focused on adults older than 50 years7-9.

The objective of the present study was to investigate the variation of self-reported knee pain, function and quality of life with age and gender in the adult population and to establish population-based reference data for the Knee injury and Osteoarthritis Outcome Score (KOOS).

Methods
Design and data collection
A population-based sample was randomly chosen from the National Population Records for the region Skåne of Southern Sweden. All persons in Sweden are registered in the National Population Records which is updated every six weeks. Skåne holds approximately 1/9 of the Swedish population and include both urban and rural communities. A simple sampling method was used and the Knee Injury and Osteoarthritis Outcome Score (KOOS) was sent to 840 persons aged 18–84 years. Each of 7 age groups (18–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84) consisted of 60 men and 60 women. The number chosen (60 men+60 women/10 year stratum) was based on experience from clinical studies using the KOOS where a clinically significant difference often is set to 10 points and standard deviations in the magnitude of 10-15-20 have been seen in different populations and at different time points following interventions. To find a clinically significant difference of 10 points (SD 20, p = 0.05, 80% power) between men and women within an age stratum, totally 120 subjects would be needed (60 M+60W).

No other characteristics besides age and gender were obtained. The KOOS questionnaire was mailed together with a covering letter explaining the purpose of the study, and a prepaid return envelope. The non-responders were reminded twice with the same covering letter as the first time and a new KOOS questionnaire and a new prepaid return envelope. The Research Ethics Committee at the Faculty of Medicine, Lund University, Sweden approved the study (LU 600–00).

Questionnaire
Knee-specific complaints were obtained by the Swedish version LK 1.0 of the Knee Injury and Osteoarthritis Outcome Score (KOOS) 4. The KOOS is a 42-item self-administered knee-specific questionnaire assessing pain (9 items), symptoms (7 items), activities of daily living (17 items), sport and recreation function (5 items) and knee-related quality of life (4 items) in five separate subscales. Each item is responded to by marking one of five response options on a Likert scale. The WOMAC LK 3.010 items are included in the first three KOOS subscales. KOOS has been validated for short- and long-term follow-up studies of knee injury and OA3-5. KOOS was considered reliable and responsive for assessment of knee complaints in a recent comparative review of knee-specific outcome measures11.

Table 1: Age-specific KOOS scores given as mean, standard deviation, median, (95%CI of the mean) for men (M) and women (W). KOOS subscales: Mean score, SD, median (95%CI of the mean) in different groups
  18 - 34 35 - 54 55 - 74 75 - 84
  M W M W M W M W
 
Pain N = 60 N = 74 N = 78 N = 80 N = 88 N = 85 N = 34 N = 33
  92.2 92.1 87.4 88.8 87.7 78.6 83.5 87.1
  11.2 14.0 17.9 18.7 17.4 25.5 23.3 18.2
  97.2 97.2 97.2 97.2 97.2 91.7 94.4 96.9
  (89.8 - 95.6) (88.8 - 95.3) (83.4 - 91.5) (84.6 - 93.0) (84.0 - 91.4) (73.1 - 84.1) (75.3 - 91.6) (80.6 - 93.5)
 
Symptoms N = 60 N = 74 N = 78 N = 82 N = 88 N = 85 N = 36 N = 34
  87.2 89.1 86.5 89.5 88.4 77.1 83.7 88.1
  13.9 13.5 16.7 14.6 17.3 24.8 19.0 14.2
  92.9 92.9 92.9 95.8 96.4 85.7 87.5 94.6
  (83.6 - 90.8) (86.0 - 92.2) (82.7 - 90.2) (86.2 - 92.7) (84.8 - 92.1) (71.7 - 82.4) (77.3 - 90.1) (83.1 - 93.0)
 
ADL N = 60 N = 74 N = 78 N = 80 N = 88 N = 85 N = 36 N = 34
  94.2 95.2 89.1 88.6 86.3 77.4 76.1 82.7
  10.0 11.6 17.6 19.7 18.8 26.2 24.8 19.5
  100 100 100 98.5 97.1 91.2 83.1 91.9
  (91.6 - 96.7) (92.5 - 97.8) (85.1 - 93.1) (84.2 - 92.9) (82.3 - 90.3) (78.8 - 83.1) (67.7 - 84.5) (75.9 - 89.6)
 
Sport/Rec N = 60 N = 74 N = 76 N = 80 N = 87 N = 84 N = 35 N = 34
  85.1 86.4 76.0 79.3 72.6 61.0 56.3 55.9
  20.8 21.1 29.5 27.7 29.9 36.9 34.7 37.3
  92.5 95.0 87.5 90.0 80 70.0 55.0 62.5
  (79.7 - 90.5) (81.5 - 91.3) (69.2 - 82.7) (73.1 - 85.4) (66.2 - 78.9) (53.0 - 69.0) (44.4 - 68.3) (42.9 - 68.9)
 
QOL N = 59 N = 74 N = 78 N = 80 N = 88 N = 85 N = 35 N = 33
  85.3 83.6 77.7 83.4 78.9 68.6 71.1 75.4
  19.2 20.2 25.4 22.0 25.4 31.4 29.0 26.9
  93.8 87.5 87.5 93.8 87.5 75.0 75.0 83.3
  (80.3 - 90.3) (78.9 - 88.3) (72.0 - 83.5) (78.5 - 88.3) (73.5 - 84.3) (61.8 - 75.4) (61.1 - 81.0) (65.9 - 85.0)

KOOS scoring
All items were scored from 0 to 4 and summed. Raw scores were then transformed to a 0 to 100 scale where 100 represent the best result. A separate score was calculated for each of the five subscales. In accordance with the users guide12, if the number of missing items was less than or equalled 2 in a subscale they were substituted by the average item value for that subscale. If more than two items of the subscale were omitted the response was considered invalid and no subscale score was calculated.

Statistical analysis
The statistical analysis was performed with SPSS for Windows 12.0 software package (SPSS Inc., Chicago, IL, USA). To increase power and minimize the number of comparisons made, the originally 7 age groups were collapsed into four age groups (18–34, 35–54, 55–74, and 75–84) when testing for differences due to gender and age. Parametric methods were used. Some of the data is not normally distributed, but the sample size in each group is large enough to apply the central limit theorem which gives normally distributed sample means. Analysis of variance and Students’ t-test with Bonferroni correction was used because of multiple comparisons.

568 subjects (68%) responded to the questionnaire. For 29 persons, more than 2 items were missing for all subscales and no scores could be calculated. Scores for at least one subscale could thus be calculated for 539 subjects or 64% (65% for women and 63% for men), Figure 1. The number of subjects who responded varied with age. 54% responded in the youngest age group and 60% in the oldest one. The highest response rate (73%) was observed among those aged 65–74. Only in that age group did men respond more frequently than women (82% vs. 65%).

Fig 1: Flow chart that details the study procedure and formation of the patient cohort

Gender-related differences
Women in the age group 55–74 reported more knee-related complaints in all the KOOS subscales than age-matched men, Figure 2. The differences were significant for the subscales Pain (p = 0.027), Symptoms (p = 0.003) and ADL function (p = 0.046).

Fig 2 : Mean KOOS scores of the subscales pain, symptoms, activities of daily living, sports/recreation, and quality of life for men and women in different age groups

Age-related differences
Age-related differences were studied separately in men and women. In men, more difficulty was seen in the oldest age group 75–84 years compared to all the younger age groups for ADL function (p < 0.025), Sport and Recreation function (p < 0.030). For QOL more difficulty was seen in the oldest age group 75–84 years compared to the youngest age group 18–34, p = 0.045, Figure 2.

In women, the age group 55–74 years reported worse outcome compared to both the younger age groups in Pain (p < 0.007), ADL (p < 0.030), Sport and Recreation (p < 0.001) and QOL (p < 0.002). Women in the oldest age group 75–84 years reported worse outcome compared to the youngest women aged 18–34 in ADL function, and compared to both the younger age groups in Sport and Recreation function (p < 0.001).

Discussion
To our knowledge this work is the first to evaluate the distribution and severity of knee complaints across the whole adult population as measured with a knee-specific outcomes measure. In the population, severity of clinically relevant knee complaints varies with age and gender.

Knee pain is common. In a study assessing general musculoskeletal pain, the 12-month prevalence of knee pain in the Dutch population 25 years old and over has been reported to be 21.9% 13. Less is known of the functional limitations that may result from knee pain. In a British population sample aged 50 and over Jinks et al. found the 12-month period prevalence of all knee pain to be 47% 7. In the same sample they also, by the use of a knee-specific questionnaire, found that 14% reported severe knee pain, 20% reported severe difficulty with at least one area of functioning and 12% reported both, indicating the importance of evaluating both function and pain.

We found functional difficulties to increase with age, supporting previous studies in the population and in knee patients 7-9, 14, 15. A strength of our study is that we obtained data from adult subjects of a wide age range and thus could see that the previously noted deterioration in knee function in elderly is gradual during the whole adult life. Previous studies on knee pain and knee function in the population and in knee patients have focused on those over 50 years of age and have thus not been able to study these aspects 7-9, 14, 15.

The decline in function with older age groups was more apparent for the subscale Sport and recreation function compared to the subscale ADL function (Fig. 2). The subscale Sport and Recreation Function holds items representing more difficult lower extremity functions not required for activities of daily living as defined by the items of the KOOS subscale ADL. The Sport and Recreation subscale is thus more sensitive to reduction of lower extremity function, something frequently seen in clinical studies 16-19. It has however been shown that these items are relevant for every other person undergoing Total Knee Replacement (mean age 71), indicating the relevance of this subscale also for older age groups 5.

The variation seen with age and gender may be due to both knee-specific and generic factors. A limitation of our study is that no data was collected on knee disease or general health status making it difficult to further explore the reasons for the variation seen. The prevalence of radiographic signs of OA increases with age which may partly explain our findings 20, 21. It is however unlikely that our results are explained by knee pathology only. In the population, musculoskeletal pain is more common in women than men 13. Sex hormones, as well as psychosocial factors, are related to increased perception of pain in women compared to men 22. The dramatically worse knee-related outcomes seen in our study in women in the age group 55–64 compared to women in the age group 45–54 may thus be related to menopause which occurs at a mean of 51.5 years 23.

Knee pain may also be part of a more widespread pain syndrome. The prevalence of widespread pain is clearly related to age with a significant increase in subjects over 50 years of age 24. In a population study, long-standing knee pain in women was more often part of a widespread pain syndrome than knee pain in men (68% vs. 40%) 25. In future studies, and in the clinic, it may be of value to assess the subject’s total body pain in order to separate subjects with knee pain only from those where knee pain is part of a widespread pain syndrome.

The generally better knee status seen in women in the oldest age group (75–84) may support the role of both knee pathology and widespread pain as explanatory factors for the variation seen with age in women. The dominating knee pathology at this age is osteoarthritis. Knee replacement is the most effective treatment in reducing pain due to osteoarthritis, and about 90% report satisfactory pain relief 26.

According to the Swedish Knee Register’s Annual Report from 200427, the prevalence of total knee replacement is highest at 80 years and it can be estimated that every twentieth Swedish woman at age 80 has a knee replacement. In a population study, the prevalence of chronic widespread pain in women was highest at age 60–64 and then dropped with increasing age25, indicating that factors not related to the knee may also contribute to the generally better knee status seen in women in the oldest age group.

We had a response rate in this study of 68% which is comparable to others 7,28. A low response rate can also bias the overall results of pain prevalence estimates since people with chronic pain are more likely to respond 25. Also, it has been shown that subjects with a previous history of knee problems have a tendency to respond to medical surveys more readily than those without 29. The variation in response rate with age and gender could be a consequence of these two issues. The supposed higher incidence of chronic pain and previous knee problems amongst responders could lead to an overall overestimation of reported problems, but only to a minor extent affect the comparisons that the conclusions are based on. When performing the a priori power calculation we did not calculate with non-responders. Correctly, we should have calculated with 35–50% non-responders and thus included 35–50% more subjects into the study to, with sufficient power, detect differences between genders within each 10 year age stratum. To deal with this shortcoming, we collapsed the original 7 age strata into 4 wider age strata for analysis of differences due to age and gender. The reference data in this study is based on the response of 539 adult men and women.

Increased precision of the confidence intervals of the means would require more subjects. The KOOS can to some extent be compared to the generic outcome measure SF-36, both instruments are scored on a 0–100 worst to best scale and the SF-36 holds subscales like Physical Function and Bodily Pain corresponding well to the KOOS subscales ADL and Pain . The Swedish normative data for the SF-36 is based on 8.930 persons 30. For comparison, the 95% confidence interval for the mean of the SF-36 subscale Physical Function of women aged 20–24 (n = 889) is 1.6 points and for women aged 75–79 (n = 150) 10 points. For the comparable KOOS subscale ADL the 95% confidence interval of the mean for women aged 18–24 (n = 36) was 4.7 points and for women aged 75–84 (n = 34) 13.7 points. It can thus be estimated that at least a 10-fold larger population-based study sample than in the current study is required to decrease the confidence intervals for the KOOS subscale significantly. It should be a matter of discussion if this precision would improve interpretation of results in clinical studies.

Conclusion
We found pain, physical function and knee-related quality of life to vary with age and gender implying the use of age and gender matched reference values for improved understanding of the outcome after interventions due to knee injury and knee OA.

Acknowledgements
The study was supported by grants from Articulum Fellowship Europe, the Swedish Rheumatism Association, The Swedish National Center for Research in Sports, The Swedish Research Council, The King Gustaf V 80-year Birthday Fund, Zoega Foundation for Medical Research, Kock Foundations and Lund University Medical Faculty and Region Skane. The authors would like to thank Ludvig Dahl for assistance with the statistical analysis.

References

  1. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, Buckwalter J, Dougados M, Ehrlich G, Lequesne M, Lohmander S, Murphy WA Jr, Rosario-Jansen T, Schwartz B, Trippel S: Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Results from a workshop. Osteoarthritis Cartilage 1996, 4:217-43.
  2. Bellamy N, Kirwan J, Boers M, Brooks P, Strand V, Tugwell P, Altman R, Brandt K, Dougados M, Lequesne M: Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip, and hand osteoarthritis. Consensus development at OMERACT III. J Rheumatol 1997, 24 :799-802.
  3. Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD: Knee Injury and Osteoarthritis Outcome Score (KOOS)–development of a self-administered outcome measure. J Orthop Sports Phys Ther 1998, 28 :88-96.
  4. Roos EM, Roos HP, Ekdahl C, Lohmander LS: Knee injury and Osteoarthritis Outcome Score (KOOS)–validation of a Swedish version. Scand J Med Sci Sports 1998, 8:439-48.
  5. Roos EM, Toksvig-Larsen S: Knee injury and Osteoarthritis Outcome Score (KOOS) – validation and comparison to the WOMAC in total knee replacement. Health Qual Life Outcomes 2003, 1:17.
  6. Demirdjian AM, Petrie SG, Guanche CA, Thomas KA: The outcomes of two knee scoring questionnaires in a normal population. Am J Sports Med 1998, 26 :46-51.
  7. Jinks C, Jordan K, Croft P: Measuring the population impact of knee pain and disability with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain 2002, 100 :55-64.
  8. Bremner-Smith AT, Ewings P, Weale AE: Knee scores in a ‘normal’ elderly population. Knee 2004, 11 :279-82.
  9. Jinks C, Jordan K, Ong BN, Croft P: A brief screening tool for knee pain in primary care (KNEST). 2. Results from a survey in the general population aged 50 and over. Rheumatology (Oxford) 2004, 43 :55-61.
  10. Bellamy N, Buchanan W, Goldsmith CH: Validation study of WOMAC: A health status instrument for measuring clinically important patient-relevant outcomes following total hip or knee arthroplasty in osteoarthritis. Orthop Rheumatol 1988, 1:95-108.
  11. Garratt AM, Brealey S, Gillespie WJ: Patient-assessed health instruments for the knee: a structured review. Rheumatology (Oxford) 2004, 43 :1414-23.
  12. www.koos.nu
  13. Picavet HS, Schouten JS: Musculoskeletal pain in the Netherlands: prevalences, consequences and risk groups, the DMC(3)-study. Pain 2003, 102 :167-78.
  14. Brinker MR, Lund PJ, Barrack RL: Demographic biases of scoring instruments for the results of total knee arthroplasty. J Bone Joint Surg Am 1997, 79 :858-65.
  15. Ritter MA, Thong AE, Davis KE, Berend ME, Meding JB, Faris PM: Long- term deterioration of joint evaluation scores. J Bone Joint Surg Br 2004, 86 :438-42.
  16. Roos EM, Roos HP, Ryd L, Lohmander LS: Substantial disability 3 months after arthroscopic partial meniscectomy: A prospective study of patient- relevant outcomes. Arthroscopy 2000, 16 :619-26.
  17. W-Dahl A, Toksvig-Larsen S, Roos EM: A 2-year prospective study of patient-relevant outcomes in patients operated on for knee osteoarthritis with tibial osteotomy. BMC Musculoskelet Disord 2005, 6:18.
  18. von Porat A, Roos EM, Roos H: High prevalence of osteoarthritis 14 years after an anterior cruciate ligament tear in male soccer players – A study of radiographic and patient-relevant outcomes. Ann Rheum Dis 2004, 63 :269-73.
  19. Roos EM, Roos HP, Lohmander LS: WOMAC Osteoarthritis Index–additional dimensions for use in subjects with post-traumatic osteoarthritis of the knee. Western Ontario and MacMaster Universities. Osteoarthritis Cartilage 1999, 7:216-21.
  20. Verbrugge LM: Women, men, and osteoarthritis. Arthritis Care Res 1995, 8:212-20.
  21. Felson DT, Nevitt MC: Estrogen and osteoarthritis: how do we explain conflicting study results? Prev Med 1999, 28 :445-8.
  22. Fillingim RB: Sex, gender, and pain: women and men really are different. Curr Rev Pain 2000, 4:24-30.
  23. McKinlay SM, Bifano NL, McKinlay JB: Smoking and age at menopause in women. Ann Intern Med 1985, 103 :350-356.
  24. Thomas E, Peat G, Harris L, Wilkie R, Croft PR: The prevalence of pain and pain interference in a general population of older adults: cross-sectional findings from the North Staffordshire Osteoarthritis Project (NorStOP). Pain 2004, 110 :361-8.
  25. Bergman S, Herrstrom P, Hogstrom K, Petersson IF, Svensson B, Jacobsson LT: Chronic musculoskeletal pain, prevalence rates, and sociodemographic associations in a Swedish population study. J Rheumatol 2001, 28 :1369-77.
  26. Robertsson O, Dunbar M, Pehrsson T, Knutson K, Lidgren L: Patient satisfaction after knee arthroplasty: a report on 27,372 knees operated on between 1981 and 1995 in Sweden. Acta Orthop Scand 2000, 71 :262-7.
  27. www.ort.lu.se/knee
  28. Croft P, Lewis M, Wynn Jones C, Coggon D, Cooper C: Health status in patients awaiting hip replacement for osteoarthritis. Rheumatology (Oxford) 2002, 41 :1001-7.
  29. Baker P, Reading I, Cooper C, Coggon D: Knee disorders in the general population and their relation to occupation. Occup Environ Med 2003, 60 :794-7.
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This article was first published in BMC Musculoskeletal Disorders 2006,
7:38 doi:10.1186/1471-2474-7-38

© 2006 Paradowski et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Regenerative Approaches to the Repair of Cartilage Defects
Author: Dr. Carola Dony, Scil Technology GmbH

Introduction
 A cartilage, or ‘osteochondral’, defect is a defect in the gristle or hyaline cartilage at the end of the bones, where the joint surface and some of the underlying bone has been damaged. Defects of this sort are usually the result of injuries caused by sports or automobile accidents. The majority of cases involve defects in the articular knee joint.

The defect tends to be a crater with deep sides and the joint cartilage cannot fill over the gap. Insufficient management of chondral defects will lead to further destructive joint disease. Next to age, mechanical factors and genetic predisposition, cartilage defects are known to be an important cause for the development of osteoarthritis in later life and there is a consensus that repairing cartilage defects at an early stage can slow down or prevent progression to arthritis. However, severe defects in weight bearing joints are notoriously difficult to treat.

Articular cartilage has a limited capacity for repair and the surgical removal of cartilage damaged as a result of trauma or focal osteoarthrosis is of little value because of the limited repair capability of the tissue. This is why for the last thirty years; research has focused on ways to provide regenerative treatments for articular cartilage damage.

Current Treatment Options
 The current common treatment for chondral defect is a reduction of pain and discomfort by lavage or shaving of the affected regions. Other approaches can include the stimulation of the intrinsic healing capacity by drilling procedures (Pridie drilling/Micro-fracture) and reconstructive methods comprising osteochondral transplantation using autografts (mosaicplasty procedures) and allografts (only in the US). Autologous chondrocyte transplantation (ACT) is also a leading new technology using artificially expanded autograft material.

Pridie Drilling / Micro-Fracture
Pridie drilling (or chondroplasty) involves the drilling of holes into the joint bone exposing the underlying marrow and releasing undifferentiated stem cells to migrate to the areas of damage. Carbon rods are then inserted to act as a scaffold directing the stem cells to the cartilage. Originally developed in the 1980s, Pridie drilling tended to produce heat and bone debris that caused further joint problems for the patient. In more recent years a related procedure, Micro-fracture, has been used instead. The subchondral bone plate is fractured to induce a ‘superclot’ which in turn forms the basis for new fibro-cartilaginous repair tissue. Following debriding of the lesion of all unstable and loose cartillage, an arthroscopic awl is used to make multiple holes throughout the defect at 3-4 mm intervals.

In this way, a super clot floods the defect space introducing stem cells, growth factors and cytokines that can induce new repair tissue. Unfortunately, while regrowth of fibro-cartillage can be induced fairly effectively using these drilling and Micro-fracture procedures, the resulting re-grown tissue does not function adequately in articular and weight-bearing joints.

Autografts and Mosaicplasty
A more recent surgical approach to the repair of articular cartilage damage has been the use of autografting, which involves harvesting cartilage from a lesser weight-bearing region as a single block and transplanting this block to the defect site. More often a modified form of this autograft procedure known as ‘Mosaicplasty’ is used. Instead of using a single block of cartilage, multiple columns are harvested and inserted side by side within the defect.

Although this approach can provide repair to chondral defects without the limitations seen in Microfracture, coverage of the defects is often limiting for use in larger defects. The procedure also necessitates the creation of new defects at the site of harvest. This secondary defect problem is avoided if allografts are used instead, as in the USA.

However, the latter approach carries the risk of rejection and long term immunological challenges that will need to be managed with appropriate pharmaceutical interventions.

Autologous Chondrocyte Transplantation: (ACT)
A more regenerative approach to the treatment and repair of cartilage defects is the use of autologous chondrocyte transplantation or ACT. A small biopsy of about 200-300 milligrams of cartilage is first harvested via arthroscopy from a less weight bearing part of the patient’s damaged joint. Cells are then isolated from the biopsy and cultured for several weeks until sufficient cells have been generated. In an open knee surgical procedure, the cartilage is first thoroughly debrided so that the defect has healthy living borders and the defect is then sealed with either a periosteal flap or an artificial collagen membrane. A suspension of the expanded cells is then injected beneath the seal to fill the gap. Although expensive, ACT is still widely used as there is an absence of marketed alternatives.

There are though significant drawbacks: ACT procedures are not clearly superior to autografts4; the additional surgical step and the need to cultivate cells is labour intensive and greatly adds to the length of time and the cost of the procedure; and in many cases the joint, following ACT procedures, also does not show appropriate mechanical stability bearing the risk that exertion can cause cartilage cells to “leak out” under the seal.

Regenerative Approaches In Development
 Many of the drawbacks to ACT result from the fact that the cells must be regrown outside the body. One avenue of research has therefore been to look for ways to accomplish this regeneration in vivo without the need for secondary surgical procedures. That is, stimulating the growth of cells directly at the cartilage defect site in the patient’s own body. Microfracture does attempt to stimulate such regrowth but as noted above the results are not convincing for the treatment of larger defects. Therefore extensive research effort in recent years has been directed to identifying treatment alternatives by using growth factors able to stimulate cartilage regeneration directly at the defect site.

The use of growth factors in regenerative cartilage repair
One of the problems that has beset the use of growth factors or anabolic peptides to stimulate the re-growth of cartilage has been the rather nonspecific nature of the available biologically active molecules. Belonging to this category are some of the products currently under development that use fibroblast growth factors (Curagen, Zymogenetics/Serono), natural peptides that mimic thrombin (OrthoLogic Corporation) or synthetic peptides that had been stated to stimulate both cartilage as well as bone re-growth (Millenium Biologix). In addition much of the field has been dominated by the use of osteoinductive proteins that produce cartilage only as a transient tissue, which might later on being replaced by bone (endochondral ossification).

While some of these approaches are early stage and published data is therefore scarce, the available literature would seem to suggest that these non-specific factors and peptides do not have the potential to appropriately control cartilage regeneration and maintenance. However, there is a validated growth factor in development that does appear to induce cartilage repair as its specific function: the cartilage derived retinoic acid sensitive protein (CD-RAP).

CD-RAP: a growth factor specific to cartilage regeneration
The cartilage derived retinoic acid sensitive protein (rhCD-RAP) is highly specific for cartilage tissue and has been shown to play a crucial role during cartilage formation in embryonic development and in adult animals. It stimulates the matrix synthesis in primary chondrocytes derived from patients with osteoarthritis and it influences the action of BMP-2 and TGF-ß3 during mesenchymal stem cell differentiation, supporting the chondrogenic phenotype while inhibiting osteogenic differentiation . The NMR structure of the protein has been published recently.6

A recent study by Scil Technology GmbH investigated the effect of rhCD-RAP on the healing of full-thickness osteochondral defects in a preclinical model. In this study it was demonstrated that treatment with CD-RAP greatly accelerated the repair of articular cartilage and improved the histological appearance of the repaired cartilage. The average total scores on the histological grading scale were significantly better for the defects treated with rhCD-RAP than for the untreated defects.

All these properties make rhCD-RAP a highly promising candidate for cartilage regeneration and Scil Technology is developing a product candidate using rhCD-RAP to repair cartilage defects. This highly promising product candidate (ST03) makes use of a combination of rhCD-RAP and a carrier matrix allowing for controlled release of the growth factor to the defect site. The carrier is intended to be plug-shaped for direct press fitting into the osteochondral defect, either by surgery or by minimally invasive techniques.

Conclusion
 The treatment of osteochondral defects has gone through a considerable transformation in the last half century with regenerative approaches offering the potential for the regrowth of lost cartilage to return articular joints to near normal function. The future development of growth factors offers a relatively low cost alternative to more invasive approaches like ACT. In particular, the use of cartilage-specific growth factors such as CD-RAP is especially promising.

References
  1. Johnson, L. L., 1986, Surgical arthroscopy: principles and practice. The C. V. Mosby Co., St.Louis
  2. Insall, J., 1974, Clin. Orthop. 101:61
  3. Bobic, V., 1996, Knee Surg. Sports Traumatol. Arthroscopy 3:262
  4. Hunziker, E.B., 2001, Osteoarthritis and Cartilage 10:432
  5. Dietz, U. et.al, 1996, J. Biol. Chem.271:331-3316; Xie, W.F. et. al, 1998, J. Biol. Chem. 273:5026-5032; Tscheudschilsuren, G.,2004, J. Cell. Physiol., submitted
  6. Stoll, R. et. Al, 2003, Protein Sci. 12 (3): 510


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The Physician Entrepreneur in the U.S.
Author: Dr. James K. Brannon, Founder, President
and C.E.O. of Orthopedic Sciences, Inc.

Health care and how physicians are viewed by society in America have changed. In the past, under a fee for service structure, patients sought physicians because of their academic and clinical reputations. In this environment, so called “thought-leaders” emerged, being readily recognized within the orthopaedic community. More importantly, this kind of academic prowess contributes to the axiom “publish or perish,” and consequently divides income into two categories, 1) tangible income (actual earned revenue depositable into a bank account), and 2) intangible income (recognition by peers and others as the go to physician). In the fee for service era, tangible income is not a concern, and the process of educating a physician emphasizes intangible income by focusing on publishing, research, and ethics.

Having a good reputation and being ethical is a must and a requirement for all physicians for the successful practice of medicine, but an equal amount of emphasis must be placed on one’s tangible income in order to be financially successful.

Intellectual Property
 Thought-leaders, often the authors of numerous peer reviewed publications, in medicine are not leaders without followers. When meeting a standard of care, following the thoughts of a leader may be necessary. However, a broader goal is to recognize that in America, Copyright Law protects the peer reviewed publications of the thought-leader and is a subcategory of Intellectual Property Law, IPL. IPL protects and refers to any product derived from human intellect that has value in the marketplace. IPL additionally includes as subcategories, Patent Law, Trademark Law, Trade Secret Law, and Unfair Competition Law. While peer reviewed publications in medicine may increase one’s intangible income, it is Patent Law that protects a product having utilitarian value and provides the greatest opportunity to increase one’s tangible income.

As physicians, we deemphasize Patent Law by passing this exercise onto the medical device companies, limiting our success in academic medicine to how much we publish. This prevents one from recognizing that a US patent requires just as much human intellect as that required to produce a peer reviewed journal article, and neither should be considered more credible than the other. Given that medicine is taught in an academic environment, this approach to success is carried into private practice.

Climbing the academic ladder in medicine requires peer reviewed publication success, while climbing the financial ladder in medicine requires academic and financial success, both of which are governed by law and ethics. Knowledge of the above allows the physician that has received a patent to articulate that he/she is just as valuable to a department as a colleague that has published a peer reviewed article. Patents obtained by physicians in academic medicine are often less than recognized because the university for whom the physician works knows no more how to exploit the patent for financial gain than the individual receiving the patent.

When IPL is viewed broadly, the axiom in academic medicine should be “intellectual property development or perish.”

Medical Device Manufacturers
 Health care cannot be delivered without the physician, nor can any new medical device be introduced into patient care. Importantly, many medical device manufacturers have development arms of salaried employees whose specific goal is to create a new medical device for the physician to use. Given that the salaried employees do not practice medicine, where do they get their new ideas? How many of us have participated in a plant tour of a medical device manufacturer where we are shown new devices and asked to disclose our opinions. We must understand that such information is intellectual property and it has value. One might not be able to create a successful business centered on a single piece of information, but knowledge of intellectual property law ensures that the physician is more equitably positioned to increase his/her tangible income.

While a physician may use their role as a thought-leader to increase intangible income, medical device manufacturers use thought-leaders to specifically increase tangible income. As a marketing strategy, the opinions of the thought-leaders may be tabulated onto a new brochure, or a “white paper” may be included with the new product release. We as physicians treat our patients as do our peers, however, this kind of practicing does not question conventional wisdom, and invariably pushes the “thought” of developing a new medical product into the labs of medical device companies, and consequently prevents the physician from seeing a new product opportunity that may exist in his/her own practice.

Technology Transfer
 There are numerous examples of new product ideas invented by physicians that have been successfully introduced into health care; the Swan-Ganz catheter is one example. However, we are aware of fewer examples wherein the physician developed the new product idea, and introduced it into patient care. The barriers to introduction of a new product idea by a physician hinge to some degree on how we interpret the acronym NIH. If we follow the path of the thought-leaders, NIH means National Institutes of Health and the securing of a RO1 grant of sorts to fund an institutional research project leading to a peer reviewed publication. Whereas if one defines this acronym from the perspective of a medical device manufacturer, NIH means Not Invented Here. Technology transfer is the process of converting an abstract idea into a testable product followed by its subsequent delivery to the patient’s bedside for clinical use under one of three FDA medical device classifications. Medical companies want physician ideas to the extent the new product idea has market value and synergy with any of its existing products or new product initiatives. Further, the inventor must recognize that even if he/she had developed a hip implant that could be inserted without a skin incision, a large medical device manufacturer is not likely to market an unproven product. Therefore, the transfer of any new technology into health care is the responsibility of its inventor. The fact that the company to whom the new product was presented had no interest should mean NOTHING. After all, it is the physician who determines that the new product is needed, and will ultimately prescribe its use once available.

THE FDA
 An understanding of how the FDA classifies medical devices is an important consideration in determining how, what, and when to develop a new product. The FDA uses three categories to classify medical devices:

  • Class I (General Controls)
    Example-Wheel Chair
  • Class II (General Controls and Special Controls)
    Example-Femoral Stem
  • Class III (General Controls and Premarket Approval)
    Example-Artificial Heart
Class I devices are subject to a comprehensive set of regulations applicable to all classes (General Controls), Class II devices include a requirement to meet Performance Standards (Special Controls), while Class III devices require Premarket Approval or PMA. Unless an exemption applies, a Premarket Notification or 510(k), must be submitted to the FDA at least 90 (ninety) days prior to introduction of the new medical device into commerce. In the 510(k) process, the manufacturer claims that the new medical device is substantially equivalent, SE, to a predicate device.

A determination of SE by the FDA can only be granted when the new medical device does not raise any new questions of safety and effectiveness. Importantly, however, some Class I and II devices are exempt from a 510(k) submission. Class III devices require a premarket approval or PMA, and the preparation of a PMA is far more extensive than a 510(k) and may invariably include clinical trials. The successful development of a medical product must be coordinated with the required FDA regulatory statues, as knowledge of the above allows one to manage costs and strategically choose a product idea that can be brought to market sooner rather than later.

Active And Passive Income
 The practice of medicine represents an educational process that leads to long term job security through active income. More succinctly, your presence is required to generate revenue. Using this educational process to generate passive income (your presence is not required) is what being a physician entrepreneur represents. It is interesting that a hip surgeon might perform 7 to 8 total joints per day, and push to do more by decreasing the turnover time. However, passive income might be increased by obtaining a patent on a new product idea that could be used during the total joint replacements. Investing our active income is a good way to increase passive income, and this practice should be continued, but being a physician entrepreneur involves identifying and developing a new product idea that will improve the care of the patient and simultaneously increase one’s financial success.

Thought-leaders are known for unique surgical procedures performed where they are employed. However, if their surgical procedures do not result in a product, it cannot be transferred to other institutions for a fee, and the passive income for the institution or the thought-leader will not increase. In America our system of IPL allows one to be rewarded for his/her intellectual creations, either in a tangible or intangible way. Yet it is the equal and ethical pursuit of both that ensures academic and financial success of the physician entrepreneur.

Your Practice
 Knowing the financial stability of one’s practice is the first step to being a successful physician entrepreneur. Minimizing operating expenses and properly managing accounts receivable, AR, and accounts payable, AP, ensures that sufficient cash flow is present to service debt. A poor knowledge of how to build a financially successful practice does not bode well with attempting to develop a new medical product. With the above in mind, it is easy to understand why a company may decline one’s new product idea as it seems to address the needs unique to an individual practice. Manufacturers profit from volume, whereas the physician entrepreneur’s motivation may be to improve the care of his/her patients.

The Business Model
 The fair market value of a device or service is defined as the exchange of something of value between a willing seller and a willing buyer under no pressure to complete the contemplated transaction. The lack of knowledge regarding how to bring a new medical product to market or to secure a patent makes one vulnerable to paying fees for services that may otherwise be free.

The physician’s focus on intangible income allows other organizations to develop business models centered on instructing physicians on how to. These various instructions, for a fee, range from how to invest funds, secure a patent, or how to avoid a CMS investigation for improper coding of surgical procedures. One must recognize that these services are needed, but a lack of knowledge regarding what the services should include, makes one likely to pay more than fair market value for any services rendered.

Conflict Of Interest
 Having a financial interest in a new medical product is not a conflict, but the failure to disclose such interest may be unethical and in some cases illegal. The Stark I and Stark II statutes govern over utilization and anti-kickback for patient referrals. The physicians must be knowledgeable of these laws and ensure that his/her business venture is in compliance.

Summary And Your New Medical Product
 Knowledge is power. One must be familiar with the process of technology transfer, how to secure FDA clearance or approval, how to secure a patent, but more importantly, how to do a prior art (any existing product similar to your creation) search online.

The Patent and Trademark Office can be visited at www.uspto.gov, and the FDA can be visited at www.fda.gov, none of which require a fee. Therefore, upon walking out of the operating room, one can easily determine if his/her new idea has been developed by doing a prior art search at the USPTO. Thus, with a good knowledge of the entrepreneurial process, one is prepared for the medical device manufacturers to reject your creation, as is typically the case. However, as you are the lead in the operating room, you can be knowledgeable enough to start your own medical device company and be more than its medical director. You will be its Founder/President & CEO and guide it to financial success.

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BOA 2006


British Orthopaedic Association
Annual Congress 2006

27-29 September
Scottish Exhibition and Convention Centre, Glasgow
The BOA Annual Congress is almost upon us once again, taking place at Glasgow’s Scottish International Convention Centre, a venue last visited in 2002. If you are planning on attending the congress, then make sure you have registered, which can be done by downloading the registration form from www.boa.ac.uk/boahome.

As usual, the BOA has arranged a social event and, in keeping up with recent tradition, it is co-sponsored by OPN. The Opening Reception is being held on Wednesday 27th September at Glasgow City Chambers, George Square, with coaches leaving SECC at 6pm. This will be a Civic Reception, with attendance by a representative of the Lord Provost, from 6.15pm - 7.45pm. As always, it is an informal reception that provides an opportunity to wind down and meet in a rather more relaxed atmosphere. The reception is free to all attending delegates, while guests and exhibitors can pre-order their tickets from Janet Mills on 02392 570888 at a cost of £25.

OPN are also sponsoring a surgeon at the Congress for a second year, covering the cost of their delegate fees - click here competition details. We all look forward to seeing you there.

click here for a exhibitor listing.




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