Manufacturing artificial bone allografts: a perspective

doi:10.12336/biomatertransl.2022.01.007

Biomaterials Translational ›› 2022, Vol. 3 ›› Issue (1): 65-80.doi: 10.12336/biomatertransl.2022.01.007

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Manufacturing artificial bone allografts: a perspective

Emma Steijvers, Armaan Ghei, Zhidao Xia^*()

Centre for Nanohealth, Institute of Life Science, Swansea University Medical School, Faculty of Medicine, Health and Life Science, Swansea, UK

Received:2022-02-07 Revised:2022-03-11 Accepted:2022-03-14 Online:2022-03-28 Published:2022-03-28
Contact: Zhidao Xia E-mail:z.xia@swansea.ac.uk
About author:Zhidao Xia, z.xia@swansea.ac.uk.

Abstract

Abstract:

Bone grafts have traditionally come from four sources: the patients’ own tissue (autograft), tissue from a living or cadaveric human donor (allograft), animal donors (xenograft) and synthetic artificial biomaterials (ceramics, cement, polymers, and metal). However, all of these have advantages and drawbacks. The most commercially successful bone grafts so far are allografts, which hold 57% of the current bone graft market; however, disease transmission and scarcity are still significant drawbacks limiting their use. Tissue-engineered grafts have great potential, in which human stem cells and synthetical biomaterials are combined to produce bone-like tissue in vitro, but this is yet to be approved for widespread clinical practice. It is hypothesised that artificial bone allografts can be mass-manufactured to replace conventional bone allografts through refined bone tissue engineering prior to decellularisation. This review article aims to review current literature on (1) conventional bone allograft preparation; (2) bone tissue engineering including the use of synthetic biomaterials as bone graft substitute scaffolds, combined with osteogenic stem cells in vitro; (3) potential artificial allograft manufacturing processes, including mass production of engineered bone tissue, osteogenic enhancement, decellularisation, sterilisation and safety assurance for regulatory approval. From these assessments, a practical route map for mass production of artificial allografts for clinical use is proposed.

Key words: biomaterials, bone graft, decellularisation, stem cells, tissue engineering

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Bone clean	Methods/materials	Source
Physical process	Sonication	U.S. Patent No. 5,797,871
	Pressurised flow	U.S. Patent No 5,513,662
	High pressure washing with agitation and liquid stream	U.S. Patent No. 5,333,625
	Agitation/shaker	the University of Miami Tissue Bank
	Oscillating atmospheric pressure	U.S. Patent No. 6,652,818
Chemical process	Ethanol	KR101272958B1
	Polyoxyethylene-23 lauryl ether	Allowash XG®
	(n-Butyl) phosphate, betadyne, TritonX-100/TNBP	BioCleanse®
	0.5% to 5% chlorhexidine gluconate	U.S. Patent No. 10,004,819
	Sodium hypochlorite and hydrogen peroxide	U.S. Patent No. 7,507,254
Combinational	Sonication + detergent; water and alcohol	U.S. Patent application 20080188939
	Supercritical fluid	U.S. Patent No. 5,725,579
	Explosive decompression	U.S. Patent No. 5,288,462

Bone clean	Methods/materials	Source
Physical process	Sonication	U.S. Patent No. 5,797,871
	Pressurised flow	U.S. Patent No 5,513,662
	High pressure washing with agitation and liquid stream	U.S. Patent No. 5,333,625
	Agitation/shaker	the University of Miami Tissue Bank
	Oscillating atmospheric pressure	U.S. Patent No. 6,652,818
Chemical process	Ethanol	KR101272958B1
	Polyoxyethylene-23 lauryl ether	Allowash XG®
	(n-Butyl) phosphate, betadyne, TritonX-100/TNBP	BioCleanse®
	0.5% to 5% chlorhexidine gluconate	U.S. Patent No. 10,004,819
	Sodium hypochlorite and hydrogen peroxide	U.S. Patent No. 7,507,254
Combinational	Sonication + detergent; water and alcohol	U.S. Patent application 20080188939
	Supercritical fluid	U.S. Patent No. 5,725,579
	Explosive decompression	U.S. Patent No. 5,288,462

	Method	Advantages	Drawbacks
Chemical	SDS	Complete removal of cellular components	Damages ECM: • Collagen disruption • GAG reduction
Chemical	Triton TnBP	Good preservation of the ECM	Poor cell removal efficiency
Enzymatic	DNAse	• Not damaging to the ECM • Very efficient in DNA debris elimination	Difficult to wash off tissues. Works only in combination with treatment disrupting cell membranes
	Trypsin	Efficient cell surface removal	Prolonged exposure can disrupt ECM
	EDTA	Disrupts cell adhesion to ECM	Inefficient alone, often combined with trypsin
Mechanical	Freeze/thaw	Efficient disruption of cell membranes	Does not efficiently remove cellular components & can damage ECM
Mechanical	Pressure	Increases chemical exposure and debris removal in tissues	High pressures can affect ECM integrity

	Method	Advantages	Drawbacks
Chemical	SDS	Complete removal of cellular components	Damages ECM: • Collagen disruption • GAG reduction
Chemical	Triton TnBP	Good preservation of the ECM	Poor cell removal efficiency
Enzymatic	DNAse	• Not damaging to the ECM • Very efficient in DNA debris elimination	Difficult to wash off tissues. Works only in combination with treatment disrupting cell membranes
	Trypsin	Efficient cell surface removal	Prolonged exposure can disrupt ECM
	EDTA	Disrupts cell adhesion to ECM	Inefficient alone, often combined with trypsin
Mechanical	Freeze/thaw	Efficient disruption of cell membranes	Does not efficiently remove cellular components & can damage ECM
Mechanical	Pressure	Increases chemical exposure and debris removal in tissues	High pressures can affect ECM integrity

Graft name	Vendor	Components	Cell count	Cell viability
Trinity ELITE	Orthofix Medical	Cancellous bone containing viable cells and demineralised bone	≥ 500000 cells/mL, of which > 100000 cells/mL are osteogenic cells	≥ 70%
Vivigen	DePuy Synthes	Corticocancellous chips containing lineage-committed bone cells and demineralised bone particulate	> 16000 cells/mL	96%
Cellentra	Zimmer-Biomet	Cancellous bone containing viable cells and demineralised cortical bone	≥ 250000 cells/mL in the cancellous tissue	≥ 70%
Osteocel Pro	NuVasive	Cryopreserved viable cancellous matrix and ground demineralised bone matrix	Average of 3 million cells/mL	> 85% on average
Bio4	Stryker	A cryopreserved viable bone matrix product that contains native matrix, endogenous osteoblasts and mesenchymal stem cells, and osteoinductive and angiogenic growth factors	On average, ≥ 600000 cells/mL	≥ 70%
Map3	RTI Surgical	Cortical cancellous bone chips, demineralised bone matrix and multipotent adult progenitor cell-class cells	≥ 50000 viable cells/mL of implant	Not available
Allostem	Allosource	Allogenic adult adipose-derived mesenchymal stem cells combined with partially demineralised allograft bone.	66255 viable cells/mL	Not available

Manufacturing artificial bone allografts: a perspective

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	Brand Name	Composition	Manufacturer	Price
HA, HA/TCP, TCP	Edbone	Implant synthetic bone - 75% hydroxyapatite & 25% β-tricalcium phosphate - Straumann/Megagen/Nobelbiocare/Dio	Ethoss Regeneration Ltd.	0.5 g, £39.86
	BiceraTM	Composed of HAP (60%) and β-tricalcium phosphate (40%) bioceramic which is similar to bone mineral	Hannox International Corporation	n.a.
	MASTERGRAFT®	β-Tricalcium phosphate (85%) and hydroxyapatite (15%)	Medtronic Sofamor Danek USA, Inc.	n.a.
	Syntoss	Dental implant synthetic bone graft β-tricalcium phosphate material block	Dental solution Israel	£46.80
	Kuraray	Bone graft materials (synthetic bone substitute, bioresorbable bone graft substitute β-tricalcium phosphate)	Biomaterial Department Japan	n.a.
	chronOS®	A synthetic β-tricalcium phosphate bone void filler which is radiopaque, resorbable and osteoconductive	DePuy Synthes	n.a
	G Graft	Bone graft material hydroxyapatite with collagen implant dental	Rohit Enterprises, India	£32.87/mL
	Ostoden	Synthetic calcium phosphate based bone graft device	Ammdent	£22.14
	MBCP®	Synthetic bone graft substitute bioactive calcium phosphate	Biomatlante SAS, France	n.a
Silicated calcium phosphate	Osteo3	A synthetic bone graft substitute, silicated calcium phosphate	OssDsign	n.a.
Silicated calcium phosphate	Actifuse^TM	Silicated calcium phosphate	ApaTech Limited	n.a
Coral	Corebone	Bio-active coral core bone graft sterile granules	Global Dental Transfer, Israel	n.a
Coral	BoneMedik	A porous, interconnected coral structure which is compatible with human bone structure	Meta Biomed Co. Ltd.	n.a.
Xeno-graft, Bovine	Zenoss	Bovine bone graft material in blocks	Dental solution Israel	£56.40
	OSTEON^TM II	Bone void filler, synthetic bone graft + collagen type 1 (bovine)	Genoss	0.25g/ £57.28
	Biotechmat	Dental bone graft - Xenograft (Bovine) - similar to Bioss	Technology in Biomaterials	£62.02
Natural	Bio-Oss	Dental Bio Oss collagen bone graft material, natural bone grafting materials	Geistlich UK	£154.51

Mesenchymal stem cell product (company)	Approval granted (year)	Indication	Product type
Queencell (Anterogen Co. Ltd.)	South Korea (2010)	Subcutaneous tissue defects	Autologous human AT-MSC
Cellgram-AMI (Pharmicell Co. Ltd.)	South Korea (2011)	Acute myocardial infarction	Autologous human BM-MSC
Cartistem (Medipost Co. Ltd.)	South Korea (2012)	Knee articular cartilage defects	Allogeneic human UC-MSC
Cupistem (Anterogen Co. Ltd.)	South Korea (2012)	Crohn’s fistula	Autologous human BM-MSC
Prochymal, remestemcel-L (Osiris Therapeutics Inc., Mesoblast Ltd.)	Canada (2012) New Zealand (2012)	Graft versus host disease	Allogeneic human BM-MSC
Neuronata-R (Corestem Inc.)	South Korea (2014)	Amyotrophic lateral sclerosis	Autologous human BM-MSC
Temcell HS (JCR Pharmaceuticals)	Japan (2015)	Graft versus host disease	Allogeneic human BM-MSC
Stempeucel (Stempeutics Research PVT)	India (2016)	Critical limb ischemia	Allogeneic human BM-MSC
Alofisel (TiGenix NV/Takeda)	Europe (2018)	Complex perianal fistulas in Crohn’s disease	Allogeneic human AT-MSC
Stemirac (Nipro Corp)	Japan (2018)	Spinal cord injury	Autologous human BM-MSC

Source company	Product	DBM (%)	Carrier	Form	Indication
Allosource	AlloFuse	36 (putty), 29 (gel)	Reverse phase medium	Putty, gel	Bone void filler/bone graft extender
Alphatech	AlphaGRAFT	80	Acellular matrix	Paste	Bone void filler
Amend Surgical	NanoFUSE	ND	45S5 bioactive glass	Putty	Bone void filler
Bactarin International	OsteoSelect	74	Carboxymethylcellulose, phosphate-buffered saline	Putty	Bone void filler
Bactarin International	Osteosponge	100	No carrier	Block, Disc, SC, strip filler	Bone void filler
Exactech	Altiva	ND	Gelatine	Paste	Bone void filler
	Optefil	24	Gelatine	Paste	Bone void filler
	Opteform	ND	Cortical and cancellous bone chips suspended in collagen-gelatine	Paste	Bone void filler
Integra	Accell Connexus	70	Poloxamer reverse phase medium	Putty	Bone void filler/ bone graft extender
	Accell Evo3	70	Poloxamer reverse phase medium and cancellous bone chips	Putty	Bone void filler
	Accell TBM	100	No carrier	Strip	Bone void filler/ bone graft extender
	DynaGraft III	ND	Poloxamer reverse phase medium	Putty, gel	Bone void filler/ bone graft extender
	OrthoBlast	ND	Poloxamer reverse phase medium	Paste	Bone void filler/bone
	OrthoBlast II	ND	Poloxamer reverse phase medium	Putty, paste	Bone void filler/bone
Lattice Biologics	H-GENIN	100	No carrier	Putty, crush‐mix, spongeous blocks, powder	Nonmanipulated substance
LifeNet Health	Optium	ND	Glycerol	Putty, gel	Bone void filler
Medtronic	DBX	31 (putty), 26 (paste), 35 (mix), 45 (strip)	Hyaluronic acid	Putty, paste, mix, strip	Bone void filler
	GRAFTON		Unpublished	Gel, flex, putty, matrix, CRUNCH®, orthoblend, strips, paste	Bone void filler/ bone graft extender
	Osteofil	24	Collagen	Paste, strip	Bone void filler
	Progenix Plus	60	Collagen type 1 (bovine) and sodium alginate	Putty	Bone void filler/ bone graft extender/bone graft substitute
	Progenix Putty	70	Collagen type 1 (bovine) and sodium alginate	Putty	Bone void filler/ bone graft extender/bone graft substitute
	VIAGRAF	ND	Glycerol	Paste, strip	Bone void filler
Osteotech	Grafton	17 to 31	Glycerol	Paste, strip	Bone void filler/ bone graft extender/bone graft substitute
Penta Biomedical	BioSet	24	Porcine gelatine	Paste, strip, disc, with or without cancellous bone chips	Bone void filler
RTI Surgical®, Inc.	BioSet DBM	24 by weight	Porcine gelatine	Paste, strip, disc, with or without cancellous chips	Bone void filler
Stryker	AlloCraft	80	Acellular matrix	Paste	Bone void filler
Wright Medical	Allomatrix	40 to 86	Calcium sulphate	Paste	Bone void filler/bone graft extender
Wright Medical	PRO‐STIM	40	Calcium sulphate and calcium phosphate	Paste, putty	Bone void filler
Zimmer	Puros® DBM	10000	No carrier	Putty, putty with cortico‐cancellous chips	Non 510(k) regulated - non-manipulated substance
Zimmer Biomet	InterGro	40 (putty), 35 (paste)	Lecithin	Putty, paste	Bone void filler/bone graft extender
NHS Blood & Transplant: Tissue and Eye services	DBM Powder	100	No carrier	Particle size-250-710 mm jar	Light and electrostatic - To be mixed with blood to enhance osteogenesis
	DBM Paste	55	Glycerol (v/v)	Paste.1, 5, 10 mL blunt ended syringe	Bone void filler
	DBM Putty	65	Glycerol (v/v)	Putty.1, 5, 10 mL blunt ended syringe	Bone void filler

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