Methods of Conservative Intra-Articular Treatment for Osteoarthritis of the Hip and Knee

Abstract

Background

Osteoarthritis is a degenerative joint disease that is becoming increasingly common as the population ages. Conservative treatment for hip or knee osteoarthritis has been limited to pain control. Intra-articular injections for targeted local treatment have been widely used in clinical practice for many years.

Methods

This review is based on publications retrieved by a selective literature search, including recent meta-analyses, systematic reviews, randomized controlled trials (RCTs), and current guidelines.

Results

In Germany, the 12-month prevalence of osteoarthritis in adults is 17.9%. Conservative treatments are intended to alleviate symptoms and do not affect the progression of the disease. Glucocorticoids can be used to relieve otherwise intractable pain in the short term, but their prolonged use increases the risk of cartilage loss and progression of osteoarthritis. According to multiple guidelines, there is only weak evidence for the use of hyaluronic acid. Evidence does exist that high–molecular-weight hyaluronic acid may lead to better outcomes than the low–molecular-weight form. RCTs have revealed no more than short-term clinical efficacy for a variety of specific therapeutic approaches, including the use of cytokine inhibitors. Other treatments, e.g., with platelet-enriched plasma, aspirates from bone marrow or adipose tissue, or expanded mesenchymal stromal cells (MSC), have not been found to have clinically relevant long-term effects.

Conclusion

In view of the scant available evidence, further standardized RCTs will be needed to give a more comprehensive picture of the efficacy of intra-articular treatments for hip and knee osteoarthritis.

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Osteoarthritis is a chronic degenerative joint disease associated with persistent inflammation, leading to pain, limitation of motion, and loss of quality of life as the disease progresses. Prevalence of osteoarthritis is rising yearly worldwide due to the demographic development with an increasingly ageing population (e1). According to the “German Health Update” (GEDA) study 2014/2015 conducted by the Robert Koch Institute, the 12-month prevalence of osteoarthritis for adults in Germany is 17.9%. It is rising significantly with increasing age (persons 65 years of age and older: women 48.1%; men 31.2%) (e2). Common sites for developing osteoarthritis are the knee, hip, ankle, joints of the hands and feet, and the spine (e3). Risk factors for developing osteoarthritis include in particular female sex, obesity, and joint injuries (e3). According to the most recent knee and hip osteoarthritis guideline of the Association of the Scientific Medical Societies in Germany (AWMF), current conservative treatment options are primarily directed towards symptom modification, but they cannot stop progression of the disease (1, 2). The term “orthobiologics” is now commonly used in this context, although it has no uniform definition. Instead, the expression “intra-articular injection therapy” is used.

Aspects of intra-articular injection therapy

Joints are surrounded by a joint capsule lined with a synovial membrane. The synovial membrane plays an important role by producing synovial fluid which is confined within the joint space. The synovial fluid is constantly renewed. This renewal must be taken into consideration when giving intra-articular injections because, within a short space of time, the injected substance is no longer present at an effective concentration. For example, hyaluronic acid is reported to have a half-life (HL) of around 26 hours, while the HL for the topical application of glucocorticoids is only a few hours (e4). Furthermore, there is overall a low risk of infection with any form of intra-articular injection therapy, irrespective of the medication used, but the risk largely depends on the general condition of the patient with their comorbidities (for example, diabetes mellitus, immunosuppressive therapy, compromized immune system disorder) (3). Patients should be informed appropriately of the potential risks before any injection therapy.

Non-cellular treatment options

Glucocorticoids

According to the recommendations of the current AWMF guidelines on knee osteoarthritis (2018) and osteoarthritis of the hip (2019), glucocorticoids are recommended for short-acting pain relief, using the lowest possible dose for symptoms refractory to non-steroidal antirheumatics (1, 2). Based on available evidence, more recent international guidelines of the American Academy of Orthopaedic Surgeons (AAOS; 2021), the Osteoarthritis Research Society International (OARSI; 2018), and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESEO; 2019) give a limited to moderate recommendation, while the international guideline of the American College of Rheumatology/Arthritis issues a strong recommendation for osteoarthritis of the hip and knee (4– 6, e5).

No difference was found between the available glucocorticoid preparations with respect to their local effectiveness for osteoarthritis. Standard doses and a comparison of randomized controlled trials (RCTs) of various preparations may be found in the systematic review article by Neumann et al. (7). A new meta-analysis of 15 randomized controlled trials showed that the effect of glucocorticoids is rated as short-term in comparison with placebo (less than six weeks) (8). Currently available study data from the results of a meta-analysis of six RCTs show that even the use of multiple doses (2–8 injections) has no advantage over placebo (9). However, the risk of glucocorticoid-induced cartilage loss with the associated accelerated progression of the osteoarthritis is significantly increased. An RCT involving a total of 140 patients showed that triamcinolone (injection dose 40 mg) administered at three-month intervals over two years resulted in a significant cartilage volume loss (–0.21 versus 0.1 mm [–0.2; 0.03 mm]) in comparison with the control group (10).

In their cohort study of 648 patients suffering from osteoarthritis of the knee covering 48 months and comparing a group treated with corticosteroids (n = 148) with a control group (n = 536), Zeng et al. (11) discovered an increased risk of requiring joint replacement (HR 2.54 [1.81; 3.57]) in addition to significantly increased osteoarthritis progression associated with increased joint-space narrowing (hazard ratio [HR]: 3.02; 95% confidence interval [2.25; 4;05]). Caution should be exercised with the use of glucocorticoids and then only in the presence of appropriate symptoms involving effusion synovialitis. Patients should be informed about the risk of osteoarthritis progression and the acceleration of the need for joint replacement. It should also be noted that glucocorticoids increase the risk of infection through their local immunosuppressive effect (12). This is of particular importance prior to hip or knee joint replacement because, according to the data of a recent systematic review, the risk of a periprosthetic joint infection in comparison with the control group not treated with glucocorticoids is significantly increased up to three months after intra-articular glucocorticoid injection (odds ratio [OR]: 1.52 [1.37; 1.67]; p <0.01) (13).

Hyaluronic acid

According to the AWMF guidelines on knee osteoarthritis (2018) and osteoarthritis of the hip (2019), the guidelines of the ESCEO (2018) and of the ACR (2019), as well as the OARSI recommendation (2018), the efficacy of hyaluronic acid is disputed based on available evidence (4– 6, 14). Hyaluronic acid is commonly used because it has been shown to be well tolerated (15). However, a recent meta-analysis of RCTs revealed weak efficacy with respect to pain and functional improvement in comparison with intra-articular cell injection therapy (16). This network meta-analysis involved a comparison of platelet rich plasma (PRP), stem cell derivatives, and placebo (saline solution). After 12 months, there was no significant difference to placebo with respect to the clinical-course parameters “pain” on the visual analogue scale (VAS) and “functional improvement” according to the International Knee Documentation Committee (IKDC) subjective score. In a network meta-analysis of a total of 30 RCTs, Migliorini et al. (17) compared the efficacy of hyaluronic acid, PRP, corticosteroids with placebo. This article demonstrated that treatment with hyaluronic acid was not superior to intra-articular placebo with respect to pain (VAS) and function according to the WOMAC score (Western Ontario and McMaster Universities Osteoarthritis Index) after the 12-month follow-up period. Meta-analyses of RCTs over shorter follow-up intervals (two to six months) also showed the low efficacy of hyaluronic acid preparations which were not superior to placebo (18). It should be pointed out, however, that the heterogeneity of the hyaluronic acid products used could have had an impact on the study outcomes. In a meta-analysis of RCTs, Hummer et al. (19) examined the efficacy of hyaluronic acid differentiated according to molecular weight. They revealed that low-molecular hyaluronic acid (less than 750 kDa) showed no significant difference from placebo with respect to pain (VAS) (standardized mean difference, SMD –0.23 [–0.67; 0.20]), whereas high-molecular hyaluronic acid was superior to placebo (SMD –0.57 [–1.04; –0.11]). It should be noted that this study was sponsored by a pharmaceutical company and therefore cannot be considered free from conflicts of interest.

Cytokine inhibition, growth factors, and other small molecules

Proinflammatory cytokines play a decisive role in the progression of osteoarthritis (e6). Synovial macrophages play a key role in the ongoing inflammation (e7). The treatment concept is directed towards treating elevated cytokine levels by the intra-articular application of appropriate anti-cytokine antibodies. However, in a multicenter RCT, the local intra-articular application of the IL-1 beta receptor antagonist anakinra, at doses of 50 and 150 mg, demonstrated no difference from placebo with respect to pain and functional improvement of ongoing osteoarthritis of the knee (Table 1) (20). The therapeutic antagonization of the proinflammatory cytokine TNF alpha with the antibodies etanercept and adalimumab only resulted in short-term clinical effects during the cited RCTs (less than four weeks) (21, 22). An explanation for the minor or short-term effect is possibly the short half-life of synovial fluid, which does not allow a clinical effect to develop.

Table 1. Overview of the clinical results (RCTs) of intra-articular treatment methods specific for osteoarthritis.

Trial [PMID]	Active substance	Mode of action (participants)	Primary end-point (secondary end-point)	Control	KL grade	Follow-up (weeks)	Main outcome (primary end-point)
Chevalier et al. 2009 (20) [19248129]	Anakinra (50 mg, 150 mg)	IL-1 beta receptor antagonist (170)	WOMAC 4 wks. (HRPQ, EQ-5D, SF-36)	Carrier solution	4	12	No improvement in comparison with placebo at any time point (WOMAC difference from baseline 50 mg: −407 vs. −475.4; p = 0.67; 150 mg: −407 vs. −475.1; p = 0.77)
Ohtori et al. 2015 (21) [26256983]	Etanercept (10 mg)	TNF alpha receptor antagonist (39)	WOMAC and VAS 4 wks.	Hyaluronic acid	2–4	4	Improvement of WOMAC (HA 50.4 ± 11.1 vs. etanercept 42.0 ± 7.0; p = 0.038); no difference on the VAS (HA 5.8 ± 2.6 vs. etanercept 4.2 ± 2.0; p = 0.054)
Wang 2018 (22) [28840750]	Adalimumab (10 mg)	Anti-TNF alpha antibodies (56)	VAS 4 wks. (WOMAC, PGA, PhGA)	Hyaluronic acid	2–3	4	Improvement of VAS (p < 0.05), (no data available)
Lohmander et al. 2014 (24) [24740822]	Sprifermin (FGF-18) (10 μg, 30 μg, 100 μg)	Growth factor (192)	Cartilage thickness (TFTJ) after 6 and 12 mos. (WOMAC)	Placebo (unspecified)	2–3	52	Cartilage regeneration effect for 100 μg in comparison with placebo 6 mos; (placebo −0.06 mm [0.14; 0.02]; 100 μg sprifermin 0.01 mm [0.00; 0.03]; p = 0.0394); 12 mos: (placebo −0.04 mm [−0.1; 0.02]; 100 μg sprifermin 0.04 mm [0.01; 0.07]; p = 0.0072)
Eckstein et al. 2021 (23) [33962962]	Sprifermin (FGF-18) (100 μg, 30 μg)	Growth factor (442)	Cartilage thickness after 2 years (TFTJ) (WOMAC)	Placebo (unspecified)	2–3	104–260	Cartilage regeneration effect for 100 μg by 0.05 mm after 2 years maintained for 5 years (0.049 mm; 95% CI [0.00; 0.10]; p = 0.015) Pain relief for 5 years (WOMAC) in comparison with control with SMD −1.29 [−9.01; 6.43]
Schwappach et al. 2017 (25) [27684085]	LMWF-5A (4 mL)	Human serum albumin RCT (40)	WOMAC pain after 20 weeks	NaCl	2–4	20	Pain relief in comparison with baseline (WOMAC) (LMWF-5A −1.41 [SD 0.81] vs. −0.85 [SD, 0.64], p = 0.02)
Yazici et al. 2021 (26) [33588087]	Lorecitivinit (0.03 mg, 0.07 mg, 0.15 mg, 0.23 mg)	WNT-signaling pathway modulator (695/700)	NRS, WOMAC, joint space width in week 24	Carrier solution Dry needle sham	2–3	13	Improvement in NRS for 0.07 mg (SMD −0.70 [−1.34; −0.06] p = 0.031) and 0.23 mg (SMD −0.82 [−1.51; −0.12], p = 0.022), improvement of WOMAC for 0.23 mg (pain −7.36 [−14.03; −0.69], p = 0.031; function: −7.99 [−14.54; −1.45], p = 0.017), no difference in joint space width
Stevens et al. 2019 (28) [30888737]	CNTX-49975 (0.5 mg, 1 mg)	Capsaicin receptor agonist transcapsaicin (172)	WOMAC pain after 12 weeks	Carrier solution with 2% lidocaine	2–4	12–24	Improvement in the WOMAC pain score for 1 mg after 12 weeks ([LSMD] −1.6, p <0.0001) and 24 weeks ([lsmd] −1.4, p = 0.0002)

CNTX, high-purity synthetic trans-capsaicin; EQ-5D, European Quality of Life 5 Dimensions; FGF, fibroblast growth factor; HA, hyaluronic acid; HRPQ, health-related productivity; KL grade, Kellgren-Lawrence grade; LSMD, least square mean difference; LMWF-5A, low molecular weight fraction of 5% human serum albumin; NRS, numeric rating scale; PGA, patient global assessment; PhGA, physician global assessment; PMID, PubMed database unique identifier number; RCT, randomized controlled trial; SF-36, Short Form 36; SMD, standardized mean difference; TFTJ, total femorotibial joint; VAS, visual analogue scale; WNT, wingless; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Growth factors stimulate the regeneration of cartilage. In a double-blind, randomized, placebo-controlled dose-finding study, sprifermin (recombinant FGF 18) at an intra-articular dose of 100 µg applied three times a week every six months over a period of 18 months for symptomatic osteoarthritis of the knee (Kellgren-Lawrence score [KL score] 2–3) showed significant pain relief after five years (WOMAC pain compared with placebo five years SMD –1.29 [–9.01; 6.43]). Pain relief corresponded to around 50 percent of the baseline level (dose response: p = 0.673). It should be noted, however, that pain relief was also evident in the placebo group and the corrected effect was therefore low. Magnetic resonance imaging (MRT) showed a significant cartilage modifying effect (mean 0.05 mm [0.0; 0.1]; p = 0.015) in comparison with placebo (23, 24). No patient in this group required knee replacement surgery over the course of the trial (sprifermin 0 of 33; placebo: 3 of 34). Adverse events developed in equal measure in the treatment and placebo groups.

Overall, initial results of sprifermin are promising, but it is not possible to make any reliable statement about its efficacy at the moment. In a phase 3 trial over 20 weeks, human serum albumin LMWF-5A provided pain relief in comparison with placebo (Table 1) (25). No subsequent long-term studies were conducted, however. Furthermore, evidence of structural changes to the arthritic cartilage is still lacking for this therapeutic approach. Lorecivivint (SM05690) as a CLK2/DYRK1A inhibitor and Wnt pathway modulator (26) achieved pain relief on the VAS (pain) and the WOMAC osteoarthritis score during a 24-week follow-up (Table 1). A cartilage regeneration effect has so far only been demonstrated preclinically in a rat model (27). Another innovative approach to relieve osteoarthritis-associated pain is the inhibition of the TRPV1 receptor with CNTX-4975 (trans-capsaicin). In an RCT, significant pain relief was achieved for up to 24 weeks with a dose of 1 mg in comparison with placebo (Table 1) (28). A recently published randomized, double-blind, placebo-controlled phase-1 trial involving the angiopoietin-like 3-derivative LNA043 (ANGPTL3), in which 28 patients with advanced symptomatic osteoarthritis of the knee received a single injection prior to total knee replacement, demonstrated a direct effect on the osteoarthritis transcriptome signature with good tolerability by the cartilage cells over 21 days. This produced regeneration processes in cartilage and suppression of mediators of osteoarthritis progression (e8). A phase-2b trial with LNA043 has already been started. It remains to be seen whether the histologically proven disease modifying effect is also confirmed in the long-term follow-up by clinical trials. On the whole, all products in the field of cytokine inhibition, growth factors, and other small molecules have so far only been applied in studies and are not available as commercial products. However, their future therapeutic potential is to be considered high.

Cellular treatment options—point-of-care products

Platelet rich plasma

Apart from platelets, platelet rich plasma (PRP) also contains growth factors, chemokines, and cytokines, which can produce anti-inflammatory and anabolic effects inside osteoarthritic environments (e9). The current guideline of the AAOS (2021) (e5), however, expresses a limited recommendation, while ACR (2019) (6) and OARSI (2019) (4) give no recommendation for the use of PRP in osteoarthritis of the hip and knee, as the data on efficacy is currently a subject of controversy. The 15 studies assessed by the AAOS did not show any superiority of PRP over hyaluronic acid. Furthermore, one study reports of adverse effects associated with hypertension and proteinuria (29). In a recently published meta-analysis of level 1 and level 2 RCTs comparing PRP and hyaluronic acid, both treatment options showed no significant difference in the clinical parameters WOMAC, VAS, and Harris Hip Score for the treatment of hip osteoarthritis over a duration of 12 months (30). Chou et al. (31) found that in the short term (three and six months) treatment with three injections was superior to single and double application with respect to the clinical scores WOMAC and VAS. After 12 months, however, there was no significant difference between the groups. In a meta-analysis comparing alternative intra-articular treatment options (hyaluronic acid, glucocorticoid) and placebo, PRP proved to be superior with respect to clinical functional parameters of the WOMAC score. However, no structural changes were demonstrated on MRI follow-up scans which otherwise might have indicated disease-modifying effects (32). Overall, the therapeutic procedure is restricted by the fact that major differences exist between the application protocols, so that in the absence of standardization, a comparison of different studies and therefore a general recommendation for clinical use is currently not possible (33).

Aspirates

Aspirates are harvested from bone marrow and adipose tissue and are often promoted as stem cell therapy. However, it is important to point out that the proportion of mesenchymal stromal cells (MSC) in these products is very low at 0.001–0.01% (e10).

Bone-marrow aspirate concentrate

Bone marrow aspirate concentrate (BMAC) is usually harvested from the iliac crest. As with harvesting PRP, a comparison of the clinical effect of the various studies is made difficult by the heterogeneity of the study protocols (34, 35). In a systematic review, Gaul et al. (34) compared the study protocols of commercially available point-of-care devices for harvesting bone marrow concentrate. Parameters such as platelet count, hematocrit, and mesenchymal stromal cell concentration were included in the analysis of the product-specific trials. It became clear that, apart from a large number of different centrifugation protocols, quality analysis was also not conducted uniformly. The specification for the uniform characterization of the products is essential to ensure real comparability. In a randomized controlled trial comparing the efficacy of BMAC and PRP in the treatment of knee osteoarthritis in 90 patients, no superiority was demonstrated for BMAC (36). On a critical note, it must be pointed out that harvesting bone marrow is associated with a level of morbidity which should be weighed against the benefits of the treatment.

Lipoaspirates/adipose tissue

Lipoaspirates are predominantly harvested from subcutaneous adipose tissue and then processed for further use. Intra-articular injection is autologous and not homologous use, which is why it is subject to the regulations of an advanced therapy medicinal product (ATMP). There is some controversy concerning the classification of lipoaspirate infiltration into the Hoffa fat pad as an ATMP. There is a difference between mechanical fragmentation (microfragmentation, centrifugation) and enzymatic digestion with regard to processing. Overall, however, there is very high heterogeneity of the isolation protocols, which is why comparability of the individual studies is restricted (e11). Furthermore, current meta-analyses consider the therapeutic use of fat aspirates and expanded MSCs together, which does not allow an individual statement on the efficacy of fat aspirates alone (37). As regards their risk profile, the study results available do not show any increased risk for the development of adverse events when using lipoaspirates (37).

Cellular therapy options – Stem/stromal cell therapy (expanded MSCs)

The treatment of osteoarthritis with mesenchymal stem/stromal cells is a very controversial topic of discussion in the current literature (e12). This is due in particular to the large differences between the isolation protocols, MSC characterization, and the use of MSCs from different sources (adipose tissue, bone marrow, umbilical cord blood, amongst others) (e13). Overall, currently available meta-analyses of clinical trials (level 1 and level 2) show symptom-modifying effects of MSC therapy over the short term of six to twelve months. However, a disease modifying effect on osteoarthritis progression has so far not been proven (38– 40). Given the high regulatory hurdles posed by substantial processing (in vitro cell culture), which classifies MSC therapy as an ATMP, this form of therapy is not used outside of trials in German-speaking countries.

Conclusion

Intra-articular injection therapies for osteoarthritis of the hip and knee have so far not produced any long-term results demonstrating disease-modifying effects. Further studies with uniform protocols, especially those focussing on cellular therapy procedures, are needed to obtain a more comprehensive picture.

Figure 1.

Schematic overview of local intra-articular injection therapy methods subdivided into cellular and non-cellular procedures. “In clinical use“ means that the active substance has been approved and is currently being used (on-label).

EVs, extracellular vesicles; MSCs, mesenchymal stromal cells; PRP, platelet-rich plasma

Box. Regulatory aspects.

When using cellular procedures such as intra-articular PRP, the surgeon automatically becomes the manufacturer when administering these products and must notify the local authorities accordingly (e14). According to the German Medicines Act (AMG), notification involves the obligation to notify (Section 67 AMG) the manufacture of medicinal products, the manufacturing authorization (Section 13 AMG), and the harvesting and processing authorization (Section 20 b,c AMG) by the competent government authority. However, the attending physician may have himself exempted from the manufacturer’s authorization by the competent authority (Section 13 para. 2b or Section 20 d AMG) if he himself is directly responsible for the application and the products are not intended for clinical trials. The decisive factor here is whether the obtained cells are for homologous use (for the same tissue) and whether a minimal or substantial change has been made to the obtained tissue. If there is a non-homologous and/or substantial modification of the tissue, the product is subject to the regulations of an ATMP (advanced therapy medicinal product), for which no exemption from the manufacturing authorization can be applied for.

Figure 2.

Overview of intra-articular treatment options for osteoarthritis with the most important known modes of action, advantages and disadvantages of the individual procedures.

ATMP, advanced therapy medicinal products—drugs for novel treatments; MSC, mesenchymal stromal cells; PRP, platelet rich plasma; SVF, stromal vascular fraction

Table 2. Recommendations by professional societies.

Treatment method	American Academy of Orthopaedic Surgeons (AAOS 2021) (e5)	Osteoarthritis Research Society International (OARSI 2019) (4)	American College of Rheumatology/Arthritis (ACR 2019) (6)	European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarhritis and Musculosceletal Diseases (ESCEO 2019) (5)	AWMF Guideline knee osteoarthritis/osteoarthritis of the hip (2018/2019) (1, 2)
Glucocorticoids	Moderate recommendation (++) (++)	Moderate recommendation (++) (++)	Strong recommendation (+++) (+++)	Limited recommendation (+)	Moderate recommendation (++) (++)
Hyaluronic acid	Moderate recommendation (++) (++)	Moderate recommendation (++) (++)	No recommendation (-) (−)	Limited recommendation (+)	Moderate recommendation (++) (++)
PRP	Limited recommendation (+)	No recommendation (−)	No recommendation (-) (−)	No details	No details for current evidence level

PRP, platelet rich plasma

Questions on the article in issue 35–36/2023:

Methods of Conservative Intra-Articular Treatment for Osteoarthritis of the Hip and Knee

The closing date for entries is September 03, 2024. Only one answer is possible for each question.

Please select the appropriate answer.

Question 1

How high is the 12-month prevalence of osteoarthritis among the adult population in Germany?

1. approx. 0.4%

2. approx. 5%

3. approx. 9%

4. approx. 18%

5. approx. 25%

Question 2

Which of the following joints is not reported to be a common site for developing osteoarthritis?

1. knee

2. hip

3. ankle

4. spine

5. shoulder

Question 3

Which of the following patient-related parameters is a particular risk factor for developing osteoarthritis?

1. obesity

2. renal impairment

3. nicotine consumption

4. high meat consumption

5. high alcohol consumption

Question 4

How long is the half-life of hyaluronic acid in the joint space after application of an intra-articular injection?

1. approx. 12 hours

2. approx. 26 hours

3. approx. 50 hours

4. approx. 76 hours

5. approx. one week

Question 5

The text puts the case for exercising caution when using glucocorticoids. What reason is given for this?

1. the risk of an habituation effect

2. the risk of developing Cushing’s disease

3. the risk of glucocorticoid-induced cartilage loss

4. the risk of joint-space widening

5. the risk of mental health side effects

Question 6

When treating with platelet rich plasma, the attending physician automatically becomes the manufacturer. In which situation can the attending physician be exempted from a manufacturer’s licence?

1. By using homologous and not significantly altered cells

2. If the cells are intermittently cryopreserved

3. By using significantly altered cells

4. If the plasma donor is a member of the patient’s family

5. By using plasma from a blood bank

Question 7

What does the text mean by the abbreviation ATMP?

1. advanced therapeutic murine platelets

2. arthrosis therapy medicinal product

3. arthrosis therapy marrow product

4. advanced therapy medicinal products

5. arthrosis therapy medicinal platelets

Question 8

Which of the following active substances is used in Germany for cellular intra-articular treatment of osteoarthritis and is also approved for this purpose?

1. hyaluronic acid

2. glucocorticoids

3. cytokine inhibitors

4. platelet-rich plasma

5. aspirates

Question 9

Which of the following receptors serves as a point of action for the specific intra-articular treatment of osteoarthritis?

1. acetylcholine receptor

2. angiotensin receptor

3. TNF-alpha receptor

4. NMDA receptor

5. kainate receptor

Question 10

Which of the following substances is obtained through fractionation of human serum albumin?

1. LMWF-5A

2. adalimumab

3. CNTX-49975

4. anakinra

5. etanercept