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Matrix-associated stem cell transplantation (mast) in chondral defects of the 1st metatarsophalangeal joint is safe and effective—2-year-follow-up in 20 patients

FAS-937; No. of Pages 6 Contents lists available at Foot and Ankle Surgery Matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint is safe and effective—2-year-follow-up in 20 patients Martinus Richter MD, PhDStefan Zech MD, Stefan Andreas Meissner MD Department for Foot and Ankle Surgery Rummelsberg and Nuremberg, Germany The aim of the study was to assess the 2-year-follow-up of matrix-associated stem cell transplantation Received 3 October 2015 (MAST) in chondral defects of the 1st metatarsophalangeal joint (MTPJ).
Received in revised form 9 May 2016 In a prospective consecutive non-controlled clinical follow-up study, 20 patients with 25 chondral Accepted 11 May 2016 defect at the 1st MTPJ that were treated with MAST from October 1st, 2011 to March, 30th, 2013 were analysed. The size and location of the chondral defects range of motion (ROM), and the Visual-Analogue- Scale Foot and Ankle (VAS FA) before treatment and at follow-up were registered.
Stem cell-rich blood was harvested from the ipsilateral pelvic bone marrow and centrifuged (10 min, 1500 RPM). The supernatant was used to impregnate a collagen I/III matrix (Chondro-Guide). The matrix Matrix-associated stem cell transplantation was fixed into the chondral defect with fibrin glue.
1st metatarsophalangeal joint The age of the patients was 42 years on average (range, 35–62 years). The VAS FA before surgery was 50.5 (range, 18.3–78.4). The defects were located as follows, dorsal metatarsal head, n = 12, plantar metatarsal head, n = 5, dorsal & plantar, n = 8 (two defects, n = 5). The defect size was 0.7 cm2 (range, .5– 2.5 cm2). ROM was 10.3/0/18.88 (dorsal extension/plantar flexion). All patients completed 2-year- follow-up. VAS FA improved to 91.5 (range, 74.2–100; t-test, p < .01). ROM improved to 34.5/0/25.5 The surgical treatment including MAST led to improved clinical scores and ROM. Even though a control group is missing, we conclude that MAST is a safe and effective method for the treatment of chondral defects of the 1st MTPJ.
! 2016 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
a modification of AMIC with a potentially higher concentration of stem cells in the implanted matrix, and also as a completely new The optimal treatment for chondral defects at foot and ankle is method Most of these methods have been used for chondral debatable. The current options are distraction, debridement, defects at the ankle MAST was also used for the 1st abrasion, microfracture, antegrade or retrograde drilling, mosaic- metatarsophalangeal joint (MTPJ) with encouraging initial results plasty or osteochondral autograft transfer system (OATS), autolo- The aim of the study was to assess the 2-year-follow-up of gous chondrocyte implantation (ACI), matrix-induced autologous MAST in chondral defects of the 1st MTPJ.
chondrocyte implantation (MACI), autologous matrix-induced chondrogenesis (AMIC), allologous stem cell transplantation, allograft bone/cartilage transplantation, or matrix-associated stem cell transplantation (MAST) . MAST was described as MAST was performed as single open procedure associated with * Corresponding author at: Department for Foot and Ankle Surgery Rummelsberg other procedures. The other procedures included the standard joint and Nuremberg, Location Hospital Rummelsberg, Rummelsberg 71, 90592 Schwar- preserving surgical management for hallux rigidus like cheilect- zenbruck, Germany. Tel.: +49 9128 50 43450; fax: +49 9128 50 43260. Homepage: omy, synovectomy, arthrolysis and tenolysis . Stem cell- www foot surgery eu.
rich blood was harvested during the procedure from the ipsilateral E-mail addresses: (M. Richter).
pelvic bone marrow with a Jamshidi needle (10 ! 3 mm, Cardinal, 1268-7731/! 2016 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Richter M, et al. Matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint is safe and effective—2-year-follow-up in 20patients. Foot Ankle Surg (2016),

FAS-937; No. of Pages 6 M. Richter et al. / Foot and Ankle Surgery xxx (2016) xxx–xxx Dublin, OH, USA) and a special syringe (Arthrex-ACP1, Arthrex, Analogue Scale Foot and Ankle (VAS FA) was registered . The Naples, FL, USA) through a stab incision. The syringe was defect size and location was assessed intraoperatively. The centrifuged (10 min, 1500 rotations per minute). The supernatant defects were classified as dorsal when located above a virtual was used to impregnate a collagen I/III matrix (Chondro-Guide1, horizontal line at 50% of the metatarsal head height or diameter; Geistlich, Baden-Baden, Germany) that was cut to the size of the plantar when located below that line, or both when crossing cartilage defect before. The cartilage defect was debrided until the line. The following parameters were registered at 2-year- stable surrounding cartilage was present. Microfracturing with a follow-up: VAS FA, ROM, radiographic hallux rigidus stage and 1.6 mm Kirschner wire was performed. The matrix with stem cells was fixed into the chondral defect with fibrin glue (Tissucoll, Deerfield, IL, USA). An 8Ch drainage was inserted without suction.
Closure was performed following the local standard with layer wise closure (joint capsule, subcutaneous, skin). The postoperative Standard dynamic pedography (three trials, walking, third treatment included full weight bearing without orthosis or splint.
step, mid stance force pattern) was performed as described before Motion of the joint with MAST was restricted for two days, and . A standard platform (Emed AT1, Novel Inc., Munich, physiotherapy with motion of this joint was started at day three Germany & St. Paul, MN, USA) and software (Emed ST1, version after surgery. The patients were instructed to perform motion of 12.3.18, Novel Inc., Munich, Germany & St. Paul, MN, USA) was the joints with MAST 10 times a day for 10 min. Postoperative used. Both sides were measured. Computerised mapping to create consultations were performed at 6 weeks, 3, 12 and 24 months.
a distribution into the following foot regions was performed with show a typical case.
the standard software (Automask, version 12.3.18, Novel Inc., Munich, Germany & St. Paul, MN, USA): hindfoot, midfoot, 1st 2.2. Study design metatarsal head, 2nd metatarsal head, 3rd metatarsal head, 4th metatarsal head, 5th metatarsal head, 1st toe, 2nd toe, 3rd–5th toe.
In a prospective consecutive non-controlled clinical follow-up This mapping process does not include manual determination of study, 20 patients with 25 chondral defect at the 1st MTPJ that landmarks Parameters of 1st metatarsal head and 1st toe were treated with MAST from October 1st, 2011 to March, 30th, were compared preoperative versus follow-up 2013 were analysed. The single inclusion criteria for the study was A paired t-test was used for statistical comparison of VAS FA and the described procedure. Patients with bilateral treatment (n = 15) maximum pedographic pressures preoperatively and at follow-up, or with corrective osteotomies for hallux valgus correction or and a Chi2-test for all other parameters. Before using the paired t- others (n = 57) were excluded. No other exclusion criteria were test, the data were investigated regarding the distribution and the defined. Range of motion (ROM) was measured clinically with a data were proven to be normally distributed.
goniometer. All patients had radiographs (bilateral views (dorso- plantar and lateral) full weight bearing). The degenerative changes were classified in four degrees . Pedography was performed as described below. There were no limitations in terms of patient's Twenty patients with 25 defects were included in the study.
age and defect size. There was no clear and objective definition The age at the time of surgery was 42 years on average (range, regarding the combination of defect size, location and age. The 35–62 years), 14 (70%) were male. The VAS FA before surgery was indication for the procedure was based on patient history, clinical 50.5 on average (range, 18.3–78.4). In 12 cases (60%), the right investigation and radiographic findings (Stage 1–3) . Stage foot was affected. shows the radiographic hallux rigidus 4 was considered as contraindication for the procedure. Visual stage. The most common stage was 2 (n = 9, 45%). Mean ROM was Fig. 1. (a and b) Case with hallux rigidus stage 2. 45-year-old female; VAS FA 56.2; ROM dorsal extension/plantar flexion 10/0/208.
Please cite this article in press as: Richter M, et al. Matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint is safe and effective—2-year-follow-up in 20patients. Foot Ankle Surg (2016),

FAS-937; No. of Pages 6 M. Richter et al. / Foot and Ankle Surgery xxx (2016) xxx–xxx Fig. 2. (a–d) Hallux rigidus stage 2 (same case as with typical dorsal osteophytes and dorsally located chondral defect (1 ! 2 cm = 2 cm2; (a)). Subpart b shows the situs after removal of the osteophytes (medial and cheilectomy), debridement of the chondral defect and microfracturing. Subpart c shows the implanted MAST. Subpart d shows a lateral intraoperative fluoroscopic image with possible 908 dorsal extension in the MTPJ.
10.3/0/18.88 for dorsal extension/plantar flexion. shows replacement. All patients completed 2-year-follow-up. VAS FA the pedographic parameters. The maximum pressure was improved to 91.5 (range, 74.2–100; t-test, p < .01). ROM 237.7 kPA at the MTPJ and 807.1 kPa at the 1st toe on average.
improved to 34.5/0/25.5 (dorsal extension & plantar flexion, The defects were located as follows, dorsal metatarsal head, p < .01). The radiographic hallux rigidus stage decreased n = 12, plantar metatarsal head, n = 5, dorsal & plantar, n = 8 (two (Chi2-test, p < .01) Stage 2 was the most common preoperative- defects, n = 5). The defect size was 0.7 cm2 (range, .5–2.5 cm2).
ly, and stage 1 at 2-year-follow-up (The maximum No complications or consecutive surgeries were registered until pressure and the percentage of maximum force of the maximum follow-up, i.e. no patient was converted to fusion or total joint force of the entire foot increased at the 1st MTPJ and decreased at Fig. 3. (a and b) Case with preoperative hallux rigidus stage 2 at two-year-follow-up (same case as ). 47-year-old female; VAS FA 92.4; ROM dorsal extension/ plantar flexion 40/0/308. Hallux rigidus stage was classified 0 at follow-up.
Please cite this article in press as: Richter M, et al. Matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint is safe and effective—2-year-follow-up in 20patients. Foot Ankle Surg (2016),

FAS-937; No. of Pages 6 M. Richter et al. / Foot and Ankle Surgery xxx (2016) xxx–xxx the cells, and the MAST includes a typical centrifugation (1500 RPM Radiographic hallux rigidus stage preoperatively and at 2-year-follow-up.
for 10 min) that potentially doubles the concentration of stem cells in the supernatant to 6% . As in MACI, MAST uses a carrier or scaffold for the cells . Different scaffold are available, some with hyaluronic acid, and others with collagen . The introduced method includes a collagen matrix (Chondro-Guide1, Geistlich, Baden-Baden, Germany) . This scaffold is manufactured out of denaturated collagen from the pig, and contains collagen I and III.
The matrix has two layers (bilayer). The superficial layer is water proof, and the deep layer is porous . The superficial, water proof the 1st toe (, all p < .01) when comparing preoperative layer should maintain the cell fluid in the defect, and the deep, porous layer should contain and maintain the cells, and should integrate in part with the underlying subchondral bone The microfracturing is added to add cells and supply from the underlying bone (marrow), as use in microfracture alone . The fibrin glue is added to give sufficient initial stability for early functional after Cheilectomy, synovectomy, arthrolysis and tenolysis are the treatment Our strategy is to fit the matrix as exact and as stable standard procedure for joint preserving surgery in hallux rigidus as possible The main advantage of MAST in comparison with ACI . These studies have shown good but not optimal results and MACI is the single procedure methodology and lower cost Reasons for suboptimal results were remaining pain . The advantage in comparison with AMIC is the potential higher and functional restrictions Later conversion to arthrod- concentration of stem cells . The advantage of the Chondro- esis were described in up to 16% in the short- to midterm follow-up Guide1 in comparison with other scaffolds/matrices used (hya- . As attempt to improve the outcome, we added MAST for the luronic acid) is the more physiological content and structure . This chondral defect(s) based on our previous experience with MAST matrix gives the initial stability to allow the early stimulation of the and hallux rigidus surgery Despite many studies focused on transplanted cells by motion which induces the determination of the treatment of cartilage defects at the ankle, no such methods were transplanted stem cells into chondrocytes Furthermore, it gives utilised for the MTPJ so far Furthermore, the use of these the collagen scaffold which seems to be extremely difficult to methods in other joints of the foot have not been described so far determine from stem cells by an in vivo stimulation Very recently, one study dealing with implantation of synthetic cartilage in the 1st MTPJ was published showing good results .
4.1. Technical issues Our results are favourable and no adverse effects have been registered. The scores improved, ROM increased, and the pedo- We consider MAST as a combination of stem cell transplantation graphic parameters were normalised. This is the first study and AMIC . An almost similar method was introduced for the including validated functional investigation based on pedography ankle as completely novel method . The advantage in compari- as far as we are aware, and improvement of the investigated son with AMIC which uses peripheral blood is the higher function (gait stance phase) was shown. The radiographic hallux concentration of pluripotent cells or stem cells. No one knows the rigidus stage as proposed by Shereff was decreased at follow-up exact concentration of stem cells which varies for different age and when compared with the preoperative stage . This classifica- location . Rough estimations name 0.1% stem cells as tion is based on radiographs, and is focused on extent of concentration in the peripheral blood and 3% in the pelvic bone osteophytes and joint space. It is not surprising at all that removal marrow in young adults . This deduces that the cells should of osteophytes and cheilectomy changes the extend of osteophytes be harvested from the pelvic bone marrow which is part of MAST which is part of the classification. However, the width of the joints Centrifugation is a useful method to double the concentration of space which is also part of the classification was also changed, i.e.
widened on average at 2-year-follow-up (example ).
We think that the MAST procedure and not the osteophyte Pedographic parameters preoperatively and at 2-year-follow-up.
removal/cheilectomy is the reason for the joint space widening.
The widening of joint space after implantation of ‘‘scaffold and cells'' was not described for the ankle, 1st MTPJ and other joints MTPJ, percentage maximum before as far as we know. The used classification does not give any force of entire foot (%) direct information about the cartilage as such as sufficient MRI with thin slice thickness could give. We would be extremely interested in histological specimens of the transplants. However, no patient was undertaken surgery again so far in which histological specimens could have been harvested. Earlier histo- 1st toe, percentage maximum logical assessment from specimens from the talus gave anecdotal force of entire foot (%) but clear evidence that the transplanted cells could develop or better determine into chondrocytes, and that the implanted 1st toe, maximum pressure (kPa) collagen matrix stayed in place and acts as a scaffold for the chondrocytes as in ‘‘real'' cartilage MTPJ, 1st metatarsophalangeal joint. The individual percentages of the maximum Only one of the above mentioned studies dealing with cartilage force of the entire force represent the percentage of the maximum force measured restoration addressed the 1st MTPJ, and none included a validated in the in the corresponding area (MTPJ or 1st toe) of the maximum force of the entire outcome score which makes a comparison with our results difficult force (100% means that the maximum force of the corresponding area is similar to from a scientific point of view The single study addressing the the maximum force of the entire foot). The individual maximum pressure values mean values of the maximum pressure measured in the three 1st MTPJ compared implantation of ‘‘synthetic cartilage'' with different trial in the corresponding area (MTPJ or 1st toe).
arthrodesis, and the conclusion of the study was that implantation Please cite this article in press as: Richter M, et al. Matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint is safe and effective—2-year-follow-up in 20patients. Foot Ankle Surg (2016),

FAS-937; No. of Pages 6 M. Richter et al. / Foot and Ankle Surgery xxx (2016) xxx–xxx of ‘‘synthetic cartilage'' and arthrodesis were equivalent. When modifying the MRI at our institution, we immediately noticed the comparing length and rate of follow-up, our results have the same difference. The cartilage was clearly pictured. Furthermore, fluid typical 2-year-follow-up with a 100% follow-up rate The score content could be measured and displayed. Even lacking a scientific based results seem to be comparable based on the fact that investigation, the qualitative interpretation of changed MRI different scores were used . Regarding functional assessment, methods with smaller slice thickness implies that the modified we would again like to point out that this is the first investigation technique is much better. We conclude that only MRI with slice including validated pedographic parameters. We registered thickness of 1 mm or less is able to correctly picture ankle cartilage.
improvement of function, i.e. pressure/force distribution in the Based on our conclusion, we did not include MRI findings in gait stance phase which was not shown by the above mentioned because MRI with sufficient technical specifications (thin slice study. Our results seem to be better than with cheilectomy alone thickness) was not available at our institution for the entire follow- which was the main goal of the introduced method Es- up period. Therefore, we used our validated score as principal pecially, improvement of validated score, validated functional outcome parameter and not MRI findings assessment and low conversion rate to arthrodesis (0%) is superior In conclusion, surgical treatment including MAST led to to previously reported results of cheilectomy alone improved clinical scores, ROM, pedographic parameters and decreased radiographic hallux rigidus stage. Even though a control group is missing, we conclude that MAST is a safe and effective method for the treatment of chondral defects of the 1st MTPJ.
Limitations of the study are: small patient number, unclear indication for treatment, associated procedures, no control group, short follow-up, and missing outcome parameter for the created Conflict of interest tissue. All patients with corrective osteotomies at the forefoot and combination with MAST at the 1st MTPJ were excluded from the None of the authors or the authors´ institution received funding study because we wanted to exclude any effect of a correction on in relation to this study.
the result. More patients (n = 57) were excluded from the study due to corrective osteotomies than patients (n = 20) included without corrective osteotomies. Furthermore patients with bilateral treatment (n = 15) were excluded comprising almost as many patients as included with unilateral treatment (n = 20).
A missing control group is always a methodological shortcom- ing as in many other studies that we cannot invalidate. The follow- up time of 2 years for a modified or new technique seems appropriate. Nevertheless a longer follow-up would be desirable.
When indicating MAST, we did not follow a clear and objective definition regarding the combination of defect size, location and age. The indication was finally made intraoperatively and subjectively by the surgeon. Regarding assessment of the created tissue, we did not obtain histological specimens which would be optimal from a scientific point of view. Giannini et al. suggested to use special MRI protocols (T2) for the ankle for evaluation of the tissue at follow-up and created a score from that They suggested that an integration of both T2 mapping and Magnetic Resonance Observation of Cartilage Repair scoring permitted adequate evaluation of the repair site in the ankle Based on our experience regarding MRI based assessment of chondral lesions at the ankle, we would like to discuss the diagnostic value of MRI for chondral defects even if we did not investigate the imaging as such. In our earlier study, we noticed a high incoherence between MRI findings and intraoperative (arthro- scopic) findings when focusing on the cartilage and not on the subchondral bone situation at the ankle . This was also described earlier and for other joints So it seems clear that MRI is able to detect subchondral bone abnormalities but it is much less clear why the investigation of the cartilage is not optimal After having changed from ‘‘standard'' MRI imaging with slice thickness of 3 mm to so-called ‘‘Cartilage- mapping'' with slice thickness of 0.4 mm, we immediately realised the reason is simply technical. The normal cartilage thickness at the ankle is around 1 mm, and the same is true for the 1st MTPJ.
Using an investigating method with a larger slice thickness (‘‘standard'' MRI with 3 mm slice thickness) is technically not able to correctly picture cartilage. The created pictures show a full image but the displayed structures between the slices are calculated means from the neighbouring slices. This might be sufficient for subchondral bone structure with a diameter of 3 mm or more but not for cartilage with thickness of less than 2 mm.
When we obtained ‘‘slices'' of 0.4 mm from the ankle after Please cite this article in press as: Richter M, et al. Matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint is safe and effective—2-year-follow-up in 20patients. Foot Ankle Surg (2016), FAS-937; No. of Pages 6 M. Richter et al. / Foot and Ankle Surgery xxx (2016) xxx–xxx Please cite this article in press as: Richter M, et al. Matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint is safe and effective—2-year-follow-up in 20patients. Foot Ankle Surg (2016),

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