Early identification of patients at risk for impaired tendon healing and corresponding novel therapeutic approaches are urgent medical needs. This study aimed to clarify the role of CD3+ T-cells during acute Achilles tendon (AT) healing. Blood and hematoma aspirate were taken from 26 patients during AT reconstruction, and additional blood samples were obtained during clinical follow-up at 6, 26 and 52 weeks after surgery. T-cell subsets were analyzed by flow cytometry using CD3, CD4, CD8, CD11a, CD57 and CD28 antibodies. Clinical follow-up included functional tests, MRI assessments, and subjective questionnaires. In vitro, the functional behavior of patient-derived tenocytes was investigated in co-cultures with autologous unpolarized CD4+ or CD8+ T-cells, or IFNy-polarized CD8+ or IL17-polarized CD4+ Tcells (n=5-6). This included alterations in gene expression (qPCR), MMP secretion (ELISA), migration rate (scratch wound healing assay) or contractility (collagen gels). Analysis revealed that elevated CD4+ T-cell levels and reduced CD8+ T-cell levels (increased CD4/CD8 ratio) in hematoma aspirate and pre-operative blood were associated with inferior clinical outcomes regarding pain and function at 26 and 52 weeks. Increased levels of CD8+ -memory T-cell subpopulations in blood 6 weeks after surgery were associated with less tendon elongation. In vitro, tenocytes showed increased MMP1/2/3 levels and collagen III/I ratio in co-culture with unpolarized and/or IL17-polarized CD4+ T-cells compared to unpolarized CD8+ T-cells. This coincided with increased IL17 receptor expression in tenocytes co-cultured with CD4+ T-cells. Exposure of tenocytes to IL17-polarized CD4+ T-cells decreased their migration rate and increased their matrix contractility, especially compared to IFNy-polarized CD8+ T-cells. The CD4+ /CD8+ T-cell ratio could serve as prognostic marker for early identification of patients with impaired AT healing potential. Local reduction of CD4+ T-cell levels or their IL17 secretion represent a potential therapeutic approach to improve AT healing and to prevent weakening of the tendon ECM.

Bone regeneration is a complex but very well organized process in which the immune system has a decisive role. The adaptive immune system and its experience level (percentage of effector and memory T cells) has been proven to influence the healing cascade especially in the early healing phases. This opens the possibility of an early intervention to enhance bone healing during the primary clinical treatment. Patients stratified for possible delayed bone healing could benefit from immunomodulatory treatment approaches. In pre-clinical studies cells and signaling molecules have been identified that could represent promising candidates to help patients in need.

Mesoporous bioactive glasses (MBGs) have been widely studied as bone regeneration systems, due to their bioactivity and ability to store and release therapeutic agents with specific biological functions. The incorporation of these nanomaterials into a thermosensitive hydrogel (TSH), in which a solution undergoes a sol-gel transition under physiological conditions, represents a promising approach to design multifunctional devices able to deliver selected molecules to pathological sites. In fact, this system can perfectly fit the defect cavity shape prior to the complete gelation, and acts as a carrier for therapeutic agents prolonged release in situ. This challenging concept is the underlying idea of the MOZART project, whose objective was to develop a library of MBGs containing different therapeutic ions and drugs, to be used as a new, smart platform technology for highly targeted therapies to enhance bone healing. The aim of this work is to investigate the bone regeneration potential of MBGs containing strontium ions (pro-osteogenic) and incorporated into thermosensitive poly(etherurethane)(PEU) based on Poloxamer407. In order to further increase the pro-osteogenic response, MBGs were also loaded with N-acetylcysteine (NAC).

MBGs containing 2%mol of Sr²⁺ were prepared by an aerosol-assisted spray-drying method and NAC was loaded post-synthesis via an incipient wetness method. The PEU hydrogel (SHP407) was synthesized via a two-step procedure in nitrogen atmosphere. Particles were characterized (FE-SEM, N₂ adsorption-desorption analysis, TGA, DSC, FT-IR and XRD) and then incorporated into the hydrogel. The hybrid systems rheological properties and stability in aqueous environment at 37°C, and its ability to co-release Sr²⁺ and NAC were analysed. After preliminary biological in vitro tests, a proof-of-concept rodent study was run to assess the ability of the resulting formulation as bone healing device. X-ray at 2 and 4-weeks post-surgery and µCT-analysis were used to evaluate the healing results in a rat osteotomy model of biologically impaired healing. Then, bones were processed for histological evaluation.

Preliminary in vivo results demonstrated that incorporation of MBGs into a TSH is a promising strategy to design a multifunctional injectable formulation for in situ and sustained delivery of pro-osteogenic species enhancing bone regeneration.

Industrialized countries experience a population aging. Elderly patients, due to the experienced immunity, have a constant pro-inflammatory milieu. Little is known on how adaptive immunity impacts the tissue homeostasis and regeneration. The standardized housing of lab animals is specific pathogen free (SPF). However, this housing condition hinders antigen exposure and thus an aging of the adaptive immune system. We hypothesized that exposure to antigens and a developing adaptive immunity will impact tissue homeostasis and regeneration in mice. Mice kept under SPF housing or non-SPF were examined towards their immune status via flow cytometry, bone structure via microCT and bone competence via biomechanical torsional testing. MSCs from these mice were analyzed regarding their differentiation potential and ECM production under various immune cell signaling. Bone regeneration was analyzed in vivo in a mouse osteotomy model. The memory and effector compartment of the adaptive immunity was significantly increased in mice under non-SPF housing. This housing led to an increased femoral cortical thickness and torsional stiffness (p<0,05), whereas the tissue mineral density was not affected. The differentiation potential of stem cells under the influence of an aged immune milieu was significantly reduced. Bone formation was highly affected by the immune status and availed of a naïve immune cell milieu. Adaptive immunity directly impacts bone tissue formation, by exhibiting a constant stress, leading to structural differences in bone tissue organization as well as mechanical competence. For experimental settings, it appears highly relevant if mouse models have had the chance to develop an experienced immune system.

Recently, we could illustrate how tightly the bone and the immune system are interconnected during normal homeostasis but even stronger during bone regeneration. Specifically, the patient´s individual ratio of CD8+ effector T cells (TEFF, already identified as potential unfavorable cells for successful healing) to CD4+ regulatory T cells (TREG, one counterpart to CD8+ TEFF in controlling intratissue inflammation) prior to injury/ surgery appears to determine the healing outcome after fracture. We hypothesized that concentrating CD4+ TREG could serve as innovative therapeutic strategy to improve bone healing. We used an adoptive CD4+ TREG transfer in our well-established mouse osteotomy model. Before treatment, we identified the pre-surgery ratio of CD8+ TEFF/ CD4+ TREG by flow cytometry to characterize the healing potential of individual animals. Thereafter, we performed an adoptive CD4+ TREG transfer to reshape inflammation for supporting osteotomy healing. Across all groups, healing outcome was analyzed after 21 days post-surgery by µCT. Whereas TREG were highly supportive in SPF mice, we observed a heterogeneous clustered healing outcome in the non-SPF mice: TREG responder (improved healing outcome; p = 0.038) and TREG non-responder (impaired healing outcome; p = 0.024). Interestingly, the pre-/peri-surgery ratio of CD8+ TEFF/ CD4+ TREG was higher in the TREG non-responder (p=0.057). Thus, the amount of adoptively transferred CD4+ TREG was not sufficient to improve the healing outcome due to initial unfavorable high CD8+ TEFF/CD4+ TREG ratio. These results clearly show the importance of determining the individual immune status of each patient in the clinic before applying an immunotherapeutic approach.

Despite its intrinsic ability to regenerate form and function after injury, bone tissue can be challenged by a multitude of pathological conditions. While innovative approaches have helped to unravel the cascades of bone healing, this knowledge has so far not improved the clinical outcomes of bone defect treatment. Recent findings have allowed us to gain in-depth knowledge about the physiological conditions and biological principles of bone regeneration. Now it is time to transfer the lessons learned from bone healing to the challenging scenarios in defects and employ innovative technologies to enable biomaterial-based strategies for bone defect healing. This review aims to provide an overview on endogenous cascades of bone material formation and how these are transferred to new perspectives in biomaterial-driven approaches in bone regeneration.

Cite this article: T. Winkler, F. A. Sass, G. N. Duda, K. Schmidt-Bleek. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232–243. DOI: 10.1302/2046-3758.73.BJR-2017-0270.R1.

Patients and Methods: Between December 2005 until January 2008 34 distal humerus fractures in 33 patients were prospectively documented and treated using the angular-stable LCP distal humerus plate system from Synthes/Switzerland. Patient median age was 54 (min 14/ max 88). Fracture types were classified according to the AO classification. Extraarticular A fractures were documented in 3 (9%) cases, partial intra-articular fractures (type B) were seen in 4 (12%) patients. Complete intraarticular fractures were found in 27 (79%) cases. Three fractures were grade I° open, 6 fractures were grade II° open according to the Gustilo classification. In median after 10 months (min 8/ max 20) follow up was performed. Due to lost to follow up in one patient functional outcome was measured in 32 patients. Functional results were evaluated using the Mayo Elbow Performence Score (MEPS).

Results: According to MEPS, predominantly excellent and good results were achieved. The intent of stable fracture fixation to allow early physical therapy was reached in 31 patients. Failure of osteosynthesis making operative revision necessary occurred in 3 patients (1x implant failure, 2x loss of reduction). Mean Mayo Elbow Performance Score was 91 points (min 88.5/ max 100). Mean range of motion for extension/flexion was 110° (min 80/ max 140) and 170° (min 125/max 180) for pronation/supination. Only one patient regained unrestricted extension, mean loss of extension was 21° (min 10/ max 40). Mean Flexion up to 131° was achieved (min 125/ max 140).

Postoperative complications were seen in eight cases (implant breakage, delayed union, lost of reduction).

Conclusion: Despite postoperative complications and revision surgery, functional results achieved using the angular-stable LCP distal Humerus system are good or excellent in the majority of patients. Through angular-stable and multidirectional screw options fixation of the distal fragment is sufficient and periostal blood supply could be protected. Especially in combination of intraarticular fractures and osteoporotic bone stock the use of the LCP distal Humerus plate system is suitable and permits early physical therapy, promising a benefit for the elbow function.

*Winner of ISFR Young Investigator Award

Purpose: The aim of this study was to compare the temporal expression pattern of factors related to cartilage and bone formation and endochondral ossification during standard and delayed bone healing for a more in-depth understanding of the molecular basis of disturbed bone healing and to elucidate suitable timing for substitution of factors to stimulate the healing process.

Methods: A tibial osteotomy was performed in two groups of sheep (n=30 each) and stabilized with either a rigid external fixator leading to standard healing or with a mechanically critical one leading to delayed healing. Hematoma/callus tissue was harvested 4, 7, 14, 21 and 42 days postop. qPCR was employed to determine the expression patterns of BMPs and other molecules.

Results: Gene expressions of BMP2, BMP4, BMP7, Noggin, MMP9 and MMP13 were distinctly lower in the delayed compared to the standard healing group at several time points from day 14, whilst no differential gene expression of Coll II and Coll X was found between both groups. Among the BMPs, BMP7 showed the most markedly differential expression. The first evident difference in BMP7 expression between both groups was found at day 14 suggesting that exogen substitution in the context of a therapeutic approach should be postponed. The differential expression pattern of both MMP9 and MMP13 suggests that there might be a failure or delay in endochondral ossification in delayed bone healing.

Conclusion: Downregulation in gene expression of osteogenic BMPs and cartilage matrix degrading MMPs may account for a considerable delay of bone healing.

Aims: The purpose of this study was to determine whether patella replacement or RAP of the patella is advantageous in TKA.

Methods: 100 patients were recruited to enter a randomised, prospective, double blind clinical trial to determine the efþcacy of patellar resurfacing during total knee arthroplasty. All patients receive the same posterior cruciatesparing prosthesis, and all operations were performed by, or under the direct supervision of the þrst author. Evaluation consisted of the determination of the HSS-Score, the knee society scores, speciþc questions relating to patellafemoral symptoms, radiographs, measurement of torques and stability of one leg standing. All knees were followed at 3 month and 18 month postoperatively.

Results: There was no signiþcant difference between the two groups with regard to the HSS-Score, and the KS-scores. Excentric and concentric torques were higher in the group with RAP of the patella. One leg standing was more stable in the group with RAP of the patella. In both groups one patient complained of severe anterior knee pain. The patient with RAP of the patellar was treated successfully with secondary patella resurfacing.

Conclusions: The clinical outcome and the prevalence of anterior knee pain after TKA with the PFC-∑ knee was not inßuenced by whether or not the patella had been resurfaced. Force and balance are slightly better after TKA with RAP of the patella.

Correct alignment is important for success in total knee replacement. Currently this is achieved by a combination of intramedullary and extramedullary alignment using jigs and cutting blocks. This multicentre study evaluates the use of computer assisted planning and the interactive guidance of instruments for total knee replacement.

Prior to surgery computer scans of the hip, knee and ankle were performed of patients enrolled in the study. Pre operative planning of the position and size of the knee components was performed by the surgeon using a CT based Vector Vision Navigation System (Brain LAB AG, Heimstetten, Germany). P.F.C.x (De Puy Leeds UK) knee replacements were then implanted in 38 patients. Surgery was carried out according to the standard surgical technique using traditional instruments. Information of the planned and intraoperatively recorded position of the cutting blocks were analysed to check varus/valgus alignment, flexion/extension alignment, the amount of planned resection from both the femoral and tibial bones and the size of the components. Information from all the separate centres was sent to a central data processing base for analysis.

Results were calculated comparing the differences between the planned and performed cuts for each of the different variables studied. Graphs demonstrate the differences in the alignment between that planned by the surgical navigation system and what was actually carried out by the instrumented cuts.

Based on the data obtained from the multicentre study we have concluded that the planned position of the implants using the standard instruments was similar to that using the Vector Vision Navigation System. We believe that it is safe to proceed with surgical navigation total knee arthroplasty using the P.F.C.x total knee prosthesis with Image Guided Surgery and a further multicentre study is currently underway evaluating this.

Ultrasound screening has shown that the shoulder joint is almost always involved in rheumatoid arthritis. But only few of rheumatoid patients suffering from omarthritis are in considerable pain. Loss of strength and mobility is often compensated by the adjacent joints. Low patients demands, as pain and swelling can be treated often temporarely successfully by corticoid injections and the need of a wide exposure of the shoulder joint when performing an open synovectomy are the reasons of the low rate of synovectomies performed in rheumatoid shoulder joints. The clinical outcome after synovectomies in rheumatoid omarthritis is generally superior to those of knee synovectomies and shows a reliable reduction of pain, swelling and an increase of ROM. The surgical trauma in open synovectomy of the shoulder results in an impairment of the complex muscle co-ordination of the shoulder and a painful long-lasting aftertreatment. This disadvantages can be prevented when using arthroscopic techniques.

The advantages of the arthroscopic technique are mostly obvious in the shoulder joint. The reduced surgical trauma of the periarticular tissue leaving the proprioreception intact results in reduced postoperative pain, allowing early mobilisation and shorter rehabilitation.

Arthroscopic surgery of the shoulder is performed with the patient in beach- chair position under general anesthesia. We use a standard 5mm arthroscope and a motorised synovial resector. To prevent bleeding it is advantageous to utilise cooled non-ionic irrigation solution with epinephrin in addition pressurised by a roller pump. Synovectomy of the glenohumeral joint and of the subacromial bursa is performed via four portals. Potential hazards like injury to the periarticular vessels and nerves or damage of the joint cartilage especially in stiff shoulders can only be prevented with careful proceeding. Active and passive physiotherapy starts on the first postoperative day.

Our first series of 12 shoulder arthroscopies done 1989–1991 was followed 3. 8 years postoperatively. Swelling and pain at rest disappeared rapidly after surgery. Pain during motion took longer to subside. At the end of follow-up patients reported slight pain on motion in five shoulders. Postoperatively all patients reported improvement of pain. There was one recurrence of swelling due to bursitis. In this patient no bursectomy was done during shoulder arthroscopy, which is now done as a routine. There was subjectively and objectively an increase of strength postoperatively. ROM showed immediate postoperative improvement, although a slight reduction was noticed during the follow-up period.

In 1990–1999 we performed 52 arthroscopical synovectomies of rheumatoid shoulders. 31 shoulders could be followed by questionnaire at a mean of 6. 5years postoperatively. Pain at rest and pain on motion was improved in about 80% and 74% respectively. Recurrence of swelling was reported by 26% of the patients. Five patients has to be operated again. The clinical outcome compare favourably with the results published about open shoulder synovectomy

Five patients with large humeral cysts were treated with arthroscopic synovectomy, arthroscopically assisted curettage and bone grafting of the cyst via a small incision at the major tuberculum. Until now none of the patients suffered from humeral collaps, no shoulder has to be replaced.

In painful rheumatoid omarthritis swelling and pain can be improved reliably with arthroscopic synovectomy. The reduced surgical trauma of minimal invasive synovectomy should raise the rate of early preventive surgery.