Bone and Cartilage regeneration with cells and tissue engineering products

Enric CàceresChair Orthopaedics

Universitat Autònoma de Barcelona

The role of mesenchymal stem cells

• Management of large bone defects and cartilage loss continues to be a challenge

• Urist 1970 discovers Bone Morphogenetic Protein

• Autologous or allogeneic MSCs can be expanded and then may be loaded in the variety of scaffolds

The role of mesenchymal stem cells

MSCs Origin

•Bone marrow•Adipose tissue (including fat pad from knee)•Periostium•Synovium•Artery walls

The role of mesenchymal stem cells

The role of mesenchymal stem cells

XCEL-MT-10-02

• Lumbar fusion in degenerative surgery:

Autologous iliac graft Gold standard– Local complications– Limited amount of material

No union 5-35% (depending condition)• Alternatives:

• BMP• Mesenchyme Stem Cells

XCEL-MT-10-02

PUBMED:

Mesenchymal stem cells 26129

Mesenchymal stem cells and bone regeneration 2911

Mesenchymal stem cells and spinal fusion 86

Mesenchymal stem cells and spinal fusion, clinical trial 3

XCEL-MT-10-02

Biomaterials. 2008 Oct;29(29):3973-82. doi: 10.1016/j.biomaterials.2008.06.026. Epub 2008 Jul 18.

The clinical use of enriched bone marrow stem cells combined with porous beta-tricalcium phosphate in posterior spinal fusion.

Gan Y, Dai K, Zhang P, Tang T, Zhu Z, Lu J.

Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.

41 patients / 95% posterolateral fusion

XCEL-MT-10-02

Zhonghua Wai Ke Za Zhi. 2008 Apr 1;46(7):493-6.

Clinical study of lumbar fusion by hybrid construct of stem cells technique and biodegradable material.

[Article in Chinese]

Zhang P, Gan YK, Tang J, Hao YQ, Wang Y, Sun YH, Zhu ZA, Dai KR.

Department of Orthopaedics, Shanghai Ninth People's Hospital, School of Medicine of Shanghai Jiaotong University, Shanghai 200011, China.

Bone marrow mesenchyme stem cells hybridized with beta-tri calcium phosphate 93% fusion

Autologous iliac crest bone graft 96% fusion

11

Title: "Ex Vivo" Expanded Autologous Bone Marrow Mesenchymal Stem Cells Fixed in Allogenic Human Bone Tissue for Spinal Fusion in Spine Degenerative Disease (XCEL-MT-OSTEO-ALPHA)”

Target: Degenerative Spondylolisthesis L4-L5 degrees I-II of MeyerdingProduct: XCEL-MT-OSTEO-ALPHA

Promotion: BST (Banc de Sang i Teixits)

Source: Agencia Nacional del medicamento

XCEL-MT-10-02

XCEL-MT-10-02

Design: Phase I/II, prospective, open (blind assessment), randomized, parallel, only one dose and multicentric

Centres / IP: Vall d’Hebron, Hosp Germans Trias i Pujol, Hosp del Mar, Hosp St Pau, ICATME-Dexeus

Objectives: 1st: To evaluate viability and safety of the product Second: Assess efficacy through image (CT and XR

evaluation of fusion status at 6 and 12m) and clinical assessment( VAS, Oswestry, SF-36)

Experimental study

Lead By Mario Aguirre and Roberto Vélez,Hospital Valle Hebron)

Experimental study

Lead By Mario Aguirre and Roberto Vélez,Hospital Valle Hebron)

Experimental study

Focal cryogen insults for inducing osteonecrosis

Lead By Mario Aguirre and Roberto Vélez,Hospital Valle Hebron)

Experimental study

Histology of therapeutic model

Lead By Mario Aguirre and Roberto Vélez,Hospital Valle Hebron)

Purpose and hypothesisPurposeRandomized study, compares the spinal fusion obtained after instrumentation and the use of a biologic product (patients MSCs bone marrow fixed in human bone tissue from a donor), with the current procedure that consist in instrumented spinal fusion and the use of each patient’s bone obtained from his/her iliac crest

Working hypothesis Proposes that the tissue engineering is valid and useful technique to achieve bone regeneration avoiding iliac crest patient harvesting

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Sample: 62 Patients, age18-85a, bout sex.

Group A: Surgical fusion using autologous mesenchymal cells expanded “ex vivo” fixed in allogenic osseous matrix (XCEL-MT-OSTEO-ALPHA)”

Group B: Surgical fusion using autologous iliac graft

XCEL-MT-10-02

• Extracción

Bone marrow aspiration

Bone marrow aspiration

• Extracción

Initial harvest bone marrow

Spread Cell Stack

Microscopically assessment of the sample celularity and brooding culture

Culture and Culture and enlargementenlargement

Volume Reduction (Spin cycle place the MSCc at the bottom of the pack)

CellStacks Strict conditions

Cèl-lules mesenquimals, previes a la colonització

• Extracción

Implant: Implant: TLIF L4-L5

TLIFTLIF

Implant: Implant: TLIF L4-L5

XCEL-MT-OSTEO-ALPHAXCEL-MT-OSTEO-ALPHA

XR AssessmentXR Assessmentindependent radiologistindependent radiologist

• Molinari score by independent radiologistMolinari score by independent radiologist

CT AssessmentCT Assessmentindependent radiologistindependent radiologist

• Anterior interbody fusion, facet fusion and Anterior interbody fusion, facet fusion and inter transverse process fusioninter transverse process fusion

2014 status of the study2014 status of the study

Centre Selected

(CI signature)

Selection

Failure

Random Random On going

postIQ

Concluded

Tto A TTo B

1 15 3 8 4 10 3

2 2 9 4 5 5 3

3 3 12 1 5 6 4 2

4 4 4 2 2 2 2

5 5 1 1 1 1

41 4 19 18 22 8

007 patient007 patient

Radiologist reportPosterorolateral multiple graft around rods with continuous bridges more specially in the right side.

007007patientpatient

001 Pacient001 Pacient

BCN Trials

Process to applying MSCs for bone repair

MSCs directlyimplanted without ex vivo

expansion

BCN Experience

Non expanded MSCs

• Avoid cost and time• Depend on the number and concentration• <1000 cell per cm3 or < 30.000 cells in total • Small volumes range 2 / 4 ml in aspiration• Centrifuging the aspirate before injection • Lack of strict analysis in many current

practice

Future MCSs in Orthopedics

Looks promising as advances in• Tissue engineering• Biomaterial• Cell biology

Converge • To play a major role in the repair and

regeneration of musculoskeletal disease and injuries